page 170 Monitoring results: goals, strategic objectives and indicators
10. RESEARCH AND DEVELOPMENT
Progress towards development of tb vaccines (Indicator SO6.1)
Background
In March 1993, WHO designated tuberculosis (TB), from initial Mtb infection, prevent those infected from a disease caused by Mycobacterium tuberculosis (Mtb), progressing to active TB disease, or prevent recurrent a global public health emergency. In 2014, TB killed disease in persons who have recently completed drug more than 1.5 million people, making Mtb responsible treatment for active TB. for more deaths worldwide than any other single infectious agent. Nearly one billion people have died E&orts also are under way to improve the safety and of TB over the past centuries – an astounding number. e$cacy of BCG vaccine, which is widely administered to Ninety-"ve per cent of the TB cases and deaths occur neonates. Di&erent vaccines may be required to induce in low- and middle-income countries that comprise immune responses in di&erent populations, such as 85% of the world’s population, and represent a leading infants versus young adults, those already infected cause of death in HIV-infected individuals and women with Mtb and those co-infected with HIV. Experts of childbearing age. #e epidemic of TB in sub-Saharan in TB prevention and control mostly agree that mass Africa has been fuelled by HIV disease, while the vaccination of adolescents/young adults in high-burden increasing incidence of diabetes in Asia further threatens countries, regardless of their infection status, even with attempts at TB control. a vaccine that is only 60% e$cacious, would have the greatest public health impact in preventing Mtb One of the highest priorities of TB research is to develop transmission and subsequent TB disease. Such a vaccine vaccines that are more e$cacious for preventing TB could prevent an estimated 30–80% of incident TB cases and interrupting the cycle of TB transmission than the in high-burden settings during the "rst 35 years a*er Mycobacterium bovis -derived BCG, the only vaccine its introduction, depending on the type of protection available to protect against TB (1). Several vaccine- the vaccine a&ords (2). #is impact would save millions based strategies have been envisioned to better control of lives. TB; these include vaccines that protect individuals
Overview of current efforts
BCG is a live, attenuated vaccine that is widely which constitutes the bulk of the global morbidity and administered to infants in most areas endemic for mortality disease burden. TB. BCG has been shown to be moderately e&ective for the prevention of more serious extrapulmonary Most successful, licensed vaccines available today tuberculosis in infants and young children, such as induce neutralizing antibodies that provide protective tuberculous meningitis and miliary tuberculosis (3). immunity; however, animal studies suggest that a robust A meta-analysis of prospective trials and case–control cellular immune response is required for protection studies determined the e$cacy against pulmonary TB against Mtb infection and disease (5, 6). For this reason, in infants and adolescents at about 50% with a range the majority of current clinical TB vaccine candidates from 0 to 80% (4). When delivered to neonates, however, are based on a variety of vectors, adjuvants and antigens BCG is not e&ective in preventing adult pulmonary TB, that induce classical TH1 cytokines such as IFN-γ/ Monitoring results: goals, strategic objectives and indicators page 171
TNF-α from either CD4 + or CD8 + T-cells. At least An initial, phase IIb proof-of-concept e$cacy trial sixteen of these candidates have moved forward into randomized 2797 BCG-vaccinated infants to receive clinical studies in the past 10 years, including 13 current either ontrol or a viral-vectored vaccine boost containing candidates (7). one Mtb antigen (MVA85A) did not show better e$cacy than BCG alone against TB disease or infection #ese clinical candidates encompass a variety of vaccine (26). A large, phase IIb trial in 3573 HIV-uninfected, categories such as inactivated mycobacterial whole cell latently Mtb infected adults in Africa assessing safety, or whole-cell extracts (live recombinant BCG vaccine immunogenicity and TB disease prevention with the VPM1002, Mycobacterium w, Vaccae, DAR-901, RUTI, GlaxoSmithKline-Aeras M72 + AS01E adjuvanted MTBVAC and M. smegmatis ) (8–10), viral-vectored fusion protein vaccine completed enrolment in 2015 and candidates (vaccinia-based MVA85A, adenoviral- is ongoing. based AERAS-402 (Ad35Ag85A,B + TB10.4) and AdAg85A and in
Opportunities and challenges
Despite recent advances in the "eld, developing a TB #ere are no clear models upon which to identify the vaccine for any chosen population is fraught with “best” Mtb antigens for use in a vaccine, as many TB considerable obstacles. Most importantly, there is vaccine animal models have a narrow dynamic range no identi"ed correlate of protection that can guide of responses that do not allow for easy di&erentiation vaccine design or animal experiments, or that can be among candidates. #is limitation is being addressed used as a credible end-point in early human studies. by re"nement of mouse, guinea pig and non-human In addition, without a known e$cacious vaccine that primate models to better approximate natural infection e&ectively prevents pulmonary TB, it is impossible to by Mtb and better mimic human disease. #e use of validate an animal model as a potential surrogate. Prior low-dose challenges, sophisticated imaging techniques sensitization to mycobacteria (immune priming) is also and novel vaccine candidates (such as H56, ID93 + confounding. Lastly, due to the relatively low regional GLA-SE, cytomegalovirus-vectored and aerosolized incidence of TB, despite the high worldwide prevalence, adenovirus-vectored vaccines) have recently shown true proof-of-concept trials that use clinical end-points that the non-human primate model may potentially are by necessity very large (1000 to 35 000 subjects) and be useful to delineate the true correlates of vaccine- expensive (US$ 10 to 50 million). induced protection. page 172 Monitoring results: goals, strategic objectives and indicators
In human biomarker studies, gene expression patterns approach in which gene expression signatures are of in Current promising leads, strategies and technologies A rational approach for selection of TB vaccine area, as they induce prolonged and high levels of e&ector candidates for future studies is required (28). #ere is T-cells at the mucosal location at which the pathogen a need to ensure that candidates in the global portfolio "rst encounters the human host. Other promising leads are testing a broad variety of immune hypotheses. Tools include intranasal attenuated para-in Future directions A. Short-term goals (within two years) • Determine whether the novel BCG replacement candidates are more safe and/or e&ective than BCG in • Evaluate vaccine candidates (obtain preliminary HIV-unexposed and exposed infants. results) from pre-proof of concept trials (early • Determine whether H4 and/or BCG and at least safety and immunogenicity assessments) and two other candidates protects against sustained proof-of-concept clinical trials that may include as Mtb infection in adolescents in a high risk of end-points prevention of infection in adolescents, infection setting. prevention of recurrence in recently-treated TB • Determine whether H56 or ID93 vaccination, in adults patients and prevention of TB disease in latently- who have recently completed successful treatment infected individuals. for drug-sensitive pulmonary TB, protects against • Test aerosol vaccine strategies in humans in phase I to recurrent TB disease. IIa studies. • Have established a reproducible non-human primate • Develop improved animal models, speci"cally a low- model and use it to identify a potential correlate dose non-human primate challenge model, a non- of protection. human primate to non-human primate transmission • Have advanced a candidate demonstrating proof model and a natural transmission guinea pig model. of meaningful biological activity (in a non-human • Identify one to two antibody-based candidates to move primate model, a prevention of infection trial or into animal challenge studies to establish proof of a prevention of recurrence trial) into phase IIb concept for a role of antibody in modulating disease. prevention of TB disease e$cacy trials. • Identify optimized glycoprotein candidates and • Have a global consortium that in • Determine whether the M72 vaccine candidate protects against TB in latently-infected adults. Discussion Presentations at the 2016 Global Vaccine and clinical outcomes, the lack of a reliable and reproducible Immunization Research Forum (GVIRF) focused on the functional assay, and the lack of a human challenge current pipeline of TB vaccine candidates as well as key model. As a result of the recent failure of MVA85A in challenges and controversies in the "eld of TB vaccine the "rst e$cacy trial of a novel TB vaccine candidate research and development. Major challenges highlighted and a greater global emphasis on the need for a vaccine, were the lack of an immune correlate of protection, the TB vaccine "eld has become more ambitious to inadequate funding, poor predictive power and lack of meet these challenges. For example, the choice of standardized animal models that reliably predict human antigens and platforms being tested has broadened, page 174 Monitoring results: goals, strategic objectives and indicators and there are e&orts to develop more relevant animal #ese and other questions must be addressed during models and to evaluate di&erent modes of prevention. vaccine development to create an e$cacious TB vaccine Other encouraging developments include increasing that can be utilized e&ectively worldwide. To begin investigation of subdominant antigens/epitopes, antigens addressing these issues, multiple new endeavours have from di&erent stages of the mycobacterial life-cycle and begun, including studies of TB epidemiology in various a renewed look at the role of B cells and non-protein regions of the world as well as e&orts to sequence and antigens, and e&orts to transform current animal models analyse non-tuberculosis mycobacteria strains from into models that better represent human Mtb exposure diverse geographic TB-endemic areas. and disease. In addition, the challenging and changing nature of the In addition, the Human Challenge Consortium global TB vaccine landscape has prompted an initiative has been formed to develop a human challenge to form a neutral, expert advisory group (the Global model. #e consortium‘s objectives are signi"cant Portfolio Advisory Committee, GPAC) to assess the and varied. #ey include development of a safe progress of TB vaccines in, or progressing towards challenge strain (e.g. using auxotrophs and genetic the clinic. Discussions on the membership, terms kill switches), development of reporter methodology of reference and scope of activity for the GPAC are (e.g. via bloodborne substrates, volatile aromatics, under way with an international working group, with the or other related approaches) and integrating regulatory goal of establishing the GPAC as a functioning team guidance to move the human challenge model into within a year. clinical development. Although the chances for licensure of a new TB vaccine Signi"cant challenges in the "eld span the gamut of by 2020 have been signi"cantly diminished by the wide vaccine development activities – from funding and range of challenges faced by TB vaccine developers, resource allocation to understanding and modifying the new advances and momentum in TB vaccine the e&ects of key co-factors (e.g. diabetes mellitus, research and development suggests that the probability non-tuberculous mycobacteria exposure) on vaccine that the world will have a viable and e&ective TB vaccine response and the role of small animal models (mice, by the year 2030 has never been better. guinea pig, rabbit) in vaccine candidate evaluation. Table 10.1: Development status of current vaccine candidates Candidate name/Identier [research partners] Phase I Phase IIa Phase IIb a Phase III Ad5 Ag85A X [McMaster University, Tianjin CanSino Biotechnology Inc.] Dar-901 X [Dartmouth College, Aeras] TB/FLU-04L X [Research Institute for Biological Safety Problems] ChAdOx1.85A/MVA85A X [University of Oxford, University of Birmingham] MVA85A/MVA85A (intradermal, aerosol) X [University of Oxford] MTBVAC X [TuBerculosis Vaccine Initiative, Zaragoza, Biofabri] ID93 + GLA-SE X [Infectious Disease Research Institute, Wellcome Trust, Aeras] H1/H56:IC31 X [Statens Serum Institut, Aeras, Valneva] Monitoring results: goals, strategic objectives and indicators page 175 Candidate name/Identier [research partners] Phase I Phase IIa Phase IIb a Phase III RUTI X [Archivel Farma, S.L] H4:IC31 X [Serum Institute of India, Sano" Pasteur, Aeras] M72 + AS01E X [GlaxoSmithKline, Aeras] VPM1002 [Max Planck, Vakzine Projekt Management, TuBerculosis Vaccine X Initiative, Serum Institute of India] M. Vaccae X [Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.] a Phase II comprises studies of a candidate vaccine that are intended to result in efficacy data in the target population to whom the vaccine would be administered should it eventually by licensed. A programme of phase II studies usually defines the preferred dose, route and schedule of immunizations that are eventually evaluated for efficacy. Phase II studies also provide an expanded population assessment of the safety of the product. References 1. Barker LF, Brennan MJ, Rosenstein PK, Sado& 8. von Reyn CF, et al. Prevention of tuberculosis in JC. Tuberculosis vaccine research: the impact of bacille Calmette-Guerin-primed, HIV-infected immunology. Curr Opin Immunol. 2009; 21:331–8. adults boosted with an inactivated whole-cell 2. Abu-Raddada L, Sabatellia L, Achterberga mycobacterial vaccine. AIDS. 2010; 24 (5):675–85. JT, Sugimotoa JD, Longini IM, Dye C, doi: 10.1097/QAD.0b013e3283350f1b. et al. 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Hughes J, Abrahams D, et al. #e novel TB vaccine, 5. Chambers MA, Williams A, Gavier-Widen D, AERAS-402, induces robust and polyfunctional Whelan A, Hughes C, Hall G, et al. A guinea pig CD4 and CD8T cells in adults. Am J Respir Crit model of low-dose Mycobacterium bovis aerogenic Care Med. 2010; 181:1407–17. infection. Vet Microbiol. 2001; 80:213–26. 12. Hawkridge T, Scriba TJ, Gelderbloem S, 6. Baldwin SL, D’Souza C, Roberts AD, Kelly BP, Frank Smit E, Tameris M, Moyo S, et al. Safety and AA, Lui MA, et al. Evaluation of new vaccines in the immunogenicity of a new tuberculosis vaccine, mouse and guinea pig model of tuberculosis. Infect MVA85A, in healthy adults in South Africa. J Infect Immun. 1998; 66:2951–9. Dis. 2008; 198:544–52. 7. Kaufmann SH, Hussey G, Lambert PH. 13. McShane H, Pathan AA, Sander CR, Keating New vaccines for tuberculosis. Lancet. SM, Gilbert SC, Huygen K, et al. Recombinant 2010; 375:2110–9. modi"ed vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med. 2004; 10:1240–4. page 176 Monitoring results: goals, strategic objectives and indicators 14. Verreck FAW, Vervenne RAW, Kondova I, 21. Ho* DF, Blazevic A, Abate G, Hanekom WA, van Kralingen KW, Remarque EJ, Braskamp G, Kaplan G, Soler JH, et al. A new recombinant bacille et al. MVA.85A boosting of BCG and an attenuated, Calmette-Guerin vaccine safely induces signi"cantly phoP de"cient M. tuberculosis vaccine both show enhanced tuberculosis-speci"c immunity in human protective e$cacy against tuberculosis in rhesus volunteers. J Infect Dis. 2008; 198:1491–501. macaques. PLoS One. 2009; 4:e5264. 22. Kaufmann SHE, Gengenbacher M. Recombinant 15. Xing Z, McFarland CT, Sallenave JM, Izzo A, live vaccine candidates against tuberculosis. Wang J, McMurray DN. Intranasal mucosal boosting Curr Opin Biotechnol. 2012; 23:900–7. with an adenovirus-vectored vaccine markedly 23. Sun R, Skeiky YA, Izzo A, Dheenadhayalan V, enhances the protection of BCG-primed guinea Imam Z, Penn E, et al. Novel recombinant BCG pigs against pulmonary tuberculosis. PLoS One. expressing perfringolysin O and the over-expression 2009; 4:e5856. of key immunodominant antigens; pre-clinical 16. Verreck FAW, Vervenne RAW, Kondova I, characterization, safety and protection against van Kralingen KW, Remarque EJ, Braskamp G, et al. challenge with Mycobacterium tuberculosis . Vaccine. A de"ned tuberculosis vaccine candidate boosts 2009; 27:4412–23. BCG and protects against multidrug-resistant 24. Li Z, Zhang H, Fan X, Zhang Y, Huang J, Liu Q, Mycobacterium tuberculosis . Sci Transl Med. et al. DNA electroporation prime and protein 2010; 2:53ra74. boost strategy enhances humoral immunity of 17. Dietrich J, Aagaard C, Leah R, Olsen AW, Stryhn A, tuberculosis DNA vaccines in mice and non-human Doherty TM, et al. Exchanging ESAT6 with TB10.4 primates. Vaccine. 2006; 24:4565–8. in an Ag85B fusion molecule-based tuberculosis 25. McShane H, Hill A. Prime-boost immunisation subunit vaccine: e$cient protection and ESAT6- strategies for tuberculosis. Microbes Infect. based sensitive monitoring of vaccine e$cacy. 2005; 7:962–7. J Immunol. 2005; 174:6332–9. 26. Tameris MD, Hatherill M, Landry BS, Scriba TJ, 18. Leroux-Roels I, Leroux-Roels G, Ofori-Anyinam Snowden MA, Lockhart S, at al. Safety and e$cacy O, Moris P, De Kock E, Clement F, et al. Evaluation of MVA85A, a new tuberculosis vaccine, in infants of the safety and immunogenicity of two previously vaccinated with BCG: a randomised, antigen concentrations of the Mtb72F/AS02A placebo-controlled phase 2b trial. Lancet. candidate tuberculosis vaccine in puri"ed protein 2013; 381:1021-28. derivative-negative adults. Clin Vaccine Immunol. 27. Berry MP, Graham CM, McNab FW, Xu Z, Bloch 2010; 17:1763–71. SA, Oni T, et al. An interferon-inducible neutrophil- 19. van Dissel JT, Arend SM, Prins C, Bang P, Tingskov driven blood transcriptional signature in human PN, Lingnau K, et al. Ag85B-ESAT-6 adjuvanted tuberculosis. Nature. 2010; 466:973–7. with IC31 promotes strong and long-lived 28. Barker L, Hessel L, Walker B. Rational approach to Mycobacterium tuberculosis speci"c T cell responses selection and clinical development of TB vaccine in naive human volunteers. Vaccine. 2010; 28:3571– candidates. Tuberculosis (Edinburgh, Scotland). 81. 2012; 92:S25–9. 20. Grode L, Seiler P, Baumann S, Hess J, Brinkmann V, Nasser Eddine A, et al. Increased vaccine e$cacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J Clin Invest. 2005; 115:2472–9. Bibliography 1. Dye C, Williams BG. Eliminating human tuberculosis in the twenty-"rst century. J R Soc Interface. 2008; 5 (23):653–62. Monitoring results: goals, strategic objectives and indicators page 177 Progress towards development of malaria vaccines (Indicator SO6.1) Background According to the latest WHO estimates, there were deaths (90%) continue to occur in sub-Saharan Africa, 214 million malaria cases and 438 000 malaria deaths in with children aged under 5 years and primigravid 2015 (1). #e vast majority of clinical cases (80%) and pregnant women most a&ected. Opportunities and challenges In 2015, WHO published two preferred-product stage controlled human malaria infection studies. characteristics documents specifying the preferred Two AMA1-based vaccine approaches, associated with pro"les of malaria vaccines to achieve the new induction of immune responses displaying relatively strategic goals laid out in the WHO preferred product strong in vitro biological activity against blood-stage characteristics for malaria vaccines roadmap (2). parasite growth (as measured by the growth inhibition assay) failed to impact parasite replication rates in vivo #e evaluation of non-clinical models and assays, in the (3, 4). #ese results suggest that careful assessment of context of a search for correlates (i.e. back validation), the reliance on such in vitro assays to support vaccine has recently been informed by asexual blood- development e&orts is warranted. Promising leads, strategies and technologies Pre-erythrocytic vaccines month-old age category) (5). In some children fever resulted in febrile reactions which were accompanied In 2015, the "nal phase III study results for the RTS,S by generalized convulsive seizures, but all those a&ected vaccine candidate, which analysed vaccine e$cacy, fully recovered within seven days. #e rates of serious immunogenicity, safety, and impact of RTS,S/AS01 over adverse events seen in the trial (mainly medical events a median of 38 and 48 months of follow-up (post-dose requiring hospitalization, regardless of whether they 1) in infants and young children, respectively (including were considered to be caused by the study vaccine) were the e&ect a fourth dose of vaccine) were published comparable between the trial’s RTS,S candidate vaccine (5). Vaccination with the three-dose primary series recipients and those receiving a control vaccine – except reduced clinical malaria cases over the length of the for cases of meningitis, which were reported in low study by 26% in young children aged 5–17 months at numbers. In those cases, AEFI were seen more o*en "rst vaccination (over a median follow-up of 48 months among young children receiving RTS,S compared to the a*er "rst dose across trial sites). Among young children control, including a small number of new cases reported administered a fourth dose of RTS,S 18 months a*er a*er the fourth dose. completion of the primary series, vaccine e$cacy against all clinical malaria cases was 39% over the entire study In 2014, GlaxoSmithKline submitted an application for a period. #ese results were achieved on top of existing scienti"c opinion on the RTS,S/AS01 candidate vaccine malaria interventions, such as insecticide-treated nets, to the European Medicines Agency (EMA) under which were used by approximately 78% of the trial its Article 58 procedure. #e EMA’s Committee for participants (5). Medicinal Products for Human Use (CHMP) evaluated data on the quality, safety and e$cacy of the RTS,S/ Adverse events a*er vaccination included local reactions AS01 vaccine candidate, and in 2015 adopted a positive (such as pain or swelling) and fever, the latter observed scienti"c opinion for the vaccine, stating that its quality more frequently a*er RTS,S administration compared to and the bene"t–risk balance are considered favourable the control vaccine (31% versus 13% in the older 5–17 from a regulatory perspective and that the safety pro"le of the vaccine is acceptable. However, the EMA page 178 Monitoring results: goals, strategic objectives and indicators also requested that additional information needs be (95% CI: 67–95), compared to 63% (95% CI: 20–80) for addressed in future studies, speci"cally with respect the standard full-dose regimen, in a controlled human to (1) the timing of the fourth dose and evaluation of malaria infection study. Re-challenge showed waning the safety and e$cacy of an earlier fourth dose; (2) the e$cacy in both groups, but fractional dose boosting e$cacy and safety of multiple yearly doses and whether maintained high protection (6). #ese results were the vaccine predisposes to some degree of hypo- remarkably similar to "ndings reported in 1997, where responsiveness to sequential doses; and (3) the potential 6/7 volunteers were protected with a similar regimen utility of a delayed and fractionated third dose schedule of RTS,S/AS02 (7); this regimen was not pursued at in the target age group (see http://bit.ly/1LgqUfF). that time, as the results were generally viewed as being Subsequent to the Article 58 procedure, WHO issued a “chance” "nding in view of later studies (where the formal recommendations in January 2016, calling for fractional booster dose was not implemented), and the large-scale pilot implementations of RTS,S (see http:// non-alignment with the accepted EPI schedules, www.who.int/immunization/research/development/ for which the vaccine was intended. Further dose/ malaria_vaccine_qa/en/). regimen optimization using controlled human malaria infection is planned; in addition, a phase IIb "eld study, #e recommendations include that the pilot in young African children (aged 5–17 months at "rst implementations use the 4-dose schedule of the RTS,S/ vaccination) is scheduled to start in 2017, to evaluate the AS01 vaccine in 3–5 distinct epidemiological settings potential of the delayed, fractional regimen to prevent in sub-Saharan Africa, at subnational level, covering naturally-acquired P. falciparum infection. moderate-to-high transmission settings, with three doses administered to children between 5 and 9 months Clinical evaluation of radiation-attenuated P. falciparum of age, followed by a fourth dose 15–18 months later. sporozoites, administered by "ve intravenous doses, Further recommendations for the pilot implementations has continued. In 2016, results of a controlled human are outlined in the WHO position paper (http://www. malaria infection study to investigate durability of who.int/immunization/policy/position_papers/malaria/ homologous protection reported partial (55%; 6/11) en/). protection, one year a*er immunization with four doses (8). Results from "eld studies in endemic areas, which An alternative regimen of RTS,S/AS01—in which the will inform on the potential of the vaccine approach to third dose is delayed by six months and fractionated to confer heterologous protection in the target population, one "*h of the standard dose —achieved 87% protection are expected over the coming years. Sexual, sporogonic, and/or mosquito-stage vaccines Initial clinical studies of Pfs25-based vaccines, Over the next few years, the assessment of combination formulated with aluminium-based adjuvants, have been approaches, employing a second sexual-stage antigen disappointing; only sporadic induction of high levels of (Pfs230), as well as investigation of more potent transmission-reducing activity, as determined using the adjuvants, are expected to yield initial clinical results. standard membrane feeding assay, has been reported. Future directions Short-term goals (within two years) Development status of current vaccine candidates In general, the goals identi"ed in the previous report have been met, although there remains a chronic #e recently updated WHO “Rainbow Tables”, which underfunding of P. vivax vaccine development e&orts. summarize the status of malaria vaccine development Challenges remain in de"ning the development pathway e&orts, are available at http://bit.ly/18BbpOE. for vaccine approaches where the end-points are reduced transmission at the level of a community (i.e. sexual, sporogonic, and/or mosquito-stage-vaccines interrupting malaria parasite transmission). Monitoring results: goals, strategic objectives and indicators page 179 References 1. World malaria report 2015. Geneva: World Health 6. Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Organization; 2015. Twomey PS, Moon JE, et al. Long term e$cacy, 2. WHO preferred product characteristics for malaria safety, reactogenicity, and immunogenicity of phase vaccines. Geneva: World Health Organization; IIA, open-label, controlled study for the RTS,S/ 2015 (http://www.who.int/immunization/ AS01B malaria vaccine candidate administered as documents/innovation/WHO_IVB_14.09/en/, standard doses at 0 and 1 months and 1/5 th standard accessed 30 August 2016). dose at 7 months. In: ASTMH 64 th Annual Meeting. 3. Payne RO, et al. Demonstration of the blood- Oakbrook Terrace (IL): American Society of stage controlled human malaria infection model Tropical Medicine and Hygiene; 2015. to assess e$cacy of the Plasmodium falciparum 7. Stoute JA, et al. A preliminary evaluation of a AMA1 vaccine FMP2.1/AS01. J Infect Dis. 2016; recombinant circumsporozoite protein vaccine 213(11):1743–51. doi:10.1093/infdis/jiw039. against Plasmodium falciparum malaria . RTS,S 4. Duncan CJA, et al. Impact on malaria Malaria Vaccine Evaluation Group. N Engl J Med. parasite multiplication rates in infected 1997; 336(2):86–91. volunteers of the protein-in-adjuvant vaccine 8. Ishizuka AS, et al. Protection against malaria at AMA1-C1/alhydrogel+CPG 7909. PLoS One. 1 year and immune correlates following PfSPZ 2011; 6(7):e22271. vaccination. Nat Med. 2016; 22 (6):614–23. 5. E$cacy and safety of RTS,S/AS01 malaria vaccine doi: 10.1038/nm.4110. with or without a booster dose in infants and children in Africa: "nal results of a phase 3, individually randomised, controlled trial. Lancet. 2015; 386(9988):31-45. doi: 10.1016/S0140- 6736(15)60721-8. © WHO © page 180 Monitoring results: goals, strategic objectives and indicators Progress towards development of HIV vaccines (Indicator SO6.1) Background #e human immunode"ciency virus type 1 (HIV-1) delivery or breastfeeding; and most commonly through is causing a pandemic, characterized by a progressive sexual intercourse (2). Antiretroviral drugs in various loss of CD4+ T-cells and chronic immune activation, combinations can help control the infection (3), prevent acquired immunode"ciency syndrome or AIDS. onward transmission of HIV (4) and protect treated, #e Joint United Nations Programme on HIV/ uninfected persons at risk from infection (5). However, AIDS (UNAIDS) estimates that in 2015, 2.1 million fewer than half of people living with HIV receive were newly infected (a 5% increase from 2014), treatment and pre-exposure treatment is not widely and 1.1 million died, most of whom were in sub-Saharan available (6). Ultimately, the development of a safe and Africa (1). HIV can be transmitted via injection e&ective HIV vaccine remains a global public health of blood; from mother-to-child during pregnancy, priority that is the best hope for ending HIV/AIDS (7). Overview of current efforts Some 250 HIV vaccine candidates/regimens have been hypotheses to elicit broad cellular immune responses clinically tested since 1986 as potential preventive are in development. One focuses immune responses vaccines (8), yet as is now well known, only one has to those regions of HIV that are highly conserved and demonstrated modest e$cacy a prime-boost regimen therefore may be required for viral replicative "tness of a canarypox vector delivering gag-pol-env with a (University of Oxford, International AIDS Vaccine gp120 protein boost (ALVAC-Sano"; gp120-Vaxgen) Initiative, European & Developing Countries Clinical (9). #is RV144 trial demonstrated for the "rst time that Trials Partnership) (12){Borthwick, 2014 #10;Borthwick, a vaccine could prevent HIV acquisition, with 31.2% 2014 #13} while the other, termed “mosaic antigens” uses overall e$cacy (10). In the over "ve years of follow- in silico methods (Los Alamos National Laboratory) to on research into the possible correlates of protection, design immunogens that represent diverse sequences e$cacy was most strongly associated with the presence representing the optimal choice of epitopes from all of non-neutralizing IgG antibodies to the V1V2 region known HIV strains, for broad coverage of circulating of Env) (11). viruses (Janssen Pharmaceuticals, Beth Israel Deaconess Medical Center, National Institute of Allergy and #e extensive e&orts to understand the correlates of Infectious Diseases, Ragon Institute) (13). protection combined with the complexities of generating new clinical trial material delayed a repeat clinical study Recent technological advances in B cell immunology, until 2015/16. Now, however, a new e$cacy trial set next generation sequencing, bioinformatics and to begin in 2016 will test a similar, but clade C-based, structural biology have facilitated the generation of vaccine regimen in South Africa. #e ongoing HVTN many potent, broadly neutralizing antibodies (bNAbs). 100 preliminary immunogenicity and safety test of these Studies have identi"ed bNAb binding sites on HIV Env, vaccine candidates has set the stage for HVTN 702 solved structural characterization of Env trimer and Env to determine their e$cacy. #e trial will also include epitopes with atomic-level precision, and provided a an additional protein boost and potentially more better understanding of the ontogeny of bNAbs in HIV- potent adjuvant in order to extend the longevity of the infected individuals (14). Designing immunogens to previously-demonstrated protection. elicit these bNAbs remains a major challenge, however, though structural design is now beginning to yield more Continuing parallel e&orts are developing vaccine stable and potent immunogens (15). bNAbs are also candidates addressing the hyper-variability of HIV, being evaluated for passive prophylaxis and treatment aimed at increasing breadth of antibody and T-cell (16, 17), and for delivery by gene transfer using adeno- responses or focusing responses to conserved regions of associated virus vectors (18). Updates on additional the virus. For example, vaccines based on two di&erent strategies are presented below. Monitoring results: goals, strategic objectives and indicators page 181 Current promising leads, strategies and technologies #e HIV vaccine "eld likely will not see data emerging virus and VSV delivery of an HIV Env trimer have from the next set of e$cacy trials until 2019–2020 (see recently shown e$cacy in preclinical studies and are Table 10.2); current strategies are focused on advancing being advanced to the clinic. leading candidates through clinical development, • Antigen presentation systems and novel adjuvants: improving vaccine delivery methods and optimizing Several virus-like particle and nanoparticle the next generation of candidates entering clinical antigen presentation systems as well as novel development, which include the following. adjuvants are in development. #ey are based on advances in understanding of innate and adaptive • HIV Env trimers: Recent resolution of the structure immune linkages. of a stabilized HIV Env trimer will lead to clinical • Synthetic biology technologies: Novel DNA and mRNA evaluation of immunogens more closely mimicking the vaccines are being explored in e&orts to achieve the native Env glycoprotein. Env trimers are set to enter e$cacy of viral vectors while mitigating concerns of the clinic in 2017. anti-vector immunity. Delivery of such genetic vaccines • HIV antibody epitope-based vaccines: Recent by electroporation has shown promise in clinical trials. elucidation of at least "ve major epitopes on HIV Env • Glycobiology: Advances in glycobiology are yielding that bind bNAbs will lead to the generation of clinical important insights for HIV vaccine research, both in candidates targeting each of these epitopes, including characterization and synthesis of targets recognized glycopeptides (see also below), computationally by bNAbs, and in strategies to manipulate vaccine- derived sca&olds and novel immunogens designed to induced Fc-mediated immune responses such as bind to putative germline ancestors of the bNAbs. antibody-dependent cell-mediated virus inhibition and • Sequential immunization with di&erent immunogens: antibody-dependent cell-mediated cytotoxicity. Increased understanding of how bNAbs evolve along with virus evolution in the human host led As other proven non-vaccine prevention methods, to hypothesis that sequential immunization with such as treatment-as-prevention, voluntary medical immunogens eliciting germline responses and stepwise male circumcision and pre-exposure prophylaxis with evolved antibodies may be required to drive antibody antiretroviral drugs become more widely available, a$nity maturation. Several groups are advancing it will be more di$cult to "nd appropriate at-risk candidates and human clinical safety testing of the individuals for vaccine trials. Consultation with involved "rst immunogens, eOD-GT8 and CH505, are planned communities regarding standards of prevention for 2017. within the trials will be essential, as emphasized in the • Replication of competent viral vectors: Replicating UNAIDS good participatory practices guidelines 76 . adenovirus, poxvirus, vesiculostomatitis virus (VSV) Modelling studies indicate that a preventive HIV and CMV vectors are in preclinical and early clinical vaccine could dramatically reduce the number of new development. Research in this area will focus on infections, even if coverage is less than 50%, in low- vectors generating persistent infection, mucosal and middle-income countries (19). #e best hope for delivery and targeting of the gut-associated lymphoid ending the AIDS pandemic is to develop an e&ective, tissues all in hope of mimicking the e$cacy of a live accessible vaccine that is delivered in the context of a attenuated vaccine. CMV-simian immunode"ciency comprehensive prevention strategy. Table 10.2: Ongoing preventive HIV vaccine clinical trials ClinicalTrials.gov Trial Product Antigen Phase identier DNA Rev, Nef, Tat, p17 and p24 with more than 20 # CRO2049/ and CTL epitopes of protease, reverse transcriptase GTU-MultiHIV I NCT02075983 CUT*HIVAC001 (RT) and gp160 regions of the HAN2 HIV-1 B clade HVTN 098 PENNVAX-GP Gag, Pol, Env B I NCT02431767 DNA + Protein DNA-C CN54ENV: DNA plasmid containing the DNA-C CN54ENV; CUTHIVAC002 clade C gp140 envelope gene from HIV-1 isolate I NCT02589795 CN54gp140 CN54 76 http://ww.unaids.org/sites/default/files/media_asset/JC1853_GPP_Guidelines_2011_en_0.pdf page 182 Monitoring results: goals, strategic objectives and indicators ClinicalTrials.gov Trial Product Antigen Phase identier DNA + Adeno VRC-HIVDNA016-00-VP; DNA env-A, env-B, env-C, gag-B, pol-B, nef-B; HVTN 076 I NCT00955006 VRC-HIVADV014-00-VP Ad5 Gag-Pol Env A/B/C VRC-HIVDNA016-00-VP; DNA env A, env b, env C, gag B, pol B, nef B; HVTN 082 Ib NCT01054872 VRC-HIVADV014-00-VP Ad5 env A, env B, env C, gag B, pol B DNA + Pox DNA Gag, PR, RT, Env, Tat, Rev, Vpu; Pox Gag, HVTN 094 GEO-D03; MVA/HIV62 I NCT01571960 Evn, Pol B MVA-CMDR; DNA Mosaic DNA Nat-B Env, CON-S Env, and Mosaic Env; HVTN 106 Env; DNA CON-S env; I NCT02296541 MVA gag-pol CM 240, env CM235 DNA Nat-B env DNA + Pox + Protein DNA - CN54ENV and Protein: DNA Gag, Pol, Nef C; MVA Gag, Pol, UKHVCSpoke003 ZM96GPN; CN54gp140; I NCT01922284 Nef C; protein Enc C MVA-C SAAVI DNA-C2; SAAVI HVTN 086, SAAVI DNA gag, rev, tat, nef, env C; MVA gag, rev, tat, MVA-C; Oligomeric gp140/ I NCT01418235 103 nef env C MF59 DNA + Replicating vector HIV-MAG ; VSV-Indiana DNA gag-pol B, nef, tat, vif, env B; VSV replicating HVTN 087 I NCT01578889 HIV gag vaccine gag rVSV envC; HIV-1 nef/tat/vif, HVTN 112 VSV env C; DNA nef, tat, vif , env I NCT02654080 env pDNA vaccine DNA + Replicating vector + Pox DNA-HIV-PT123; NYVAC- DNA gag, env, nef, pol C; Pox Env gp140, Gag, HVTN 092 I NCT01783977 HIV-PT1; NYVAC-HIV-PT4 Pol-Nef C Protein Full-Length Single Chain Env gp120 B fused to N terminus of the two outer IHV01 I NCT02756208 (FLSC) domains of CD4 IPCAVD008 Trimeric gp140 Trimeric gp140 I NCT02304185 RV 328 AIDSVAX B/E Env B,E II NCT01933685 Vectored Immunoprophylaxis IAVI A003 AAV1-PG9 PG9 antibody I NCT01937455 Viral vector - Adeno Ad26.ENVA.01 Ad26.EnvA-01 Ad26 Env A I NCT01103687 Mucosal/IPCAVD003 Ad26.ENVA.01 Ad26.EnvA-01 Ad26 Env A I NCT00618605 Ad5HVR48.ENVA.01 Ad5HVR48.ENVA.01 Ad5/Ad48 Env A I NCT00695877 VRC-HIVADV027-00-VP; HVTN 083 VRC-HIVADV052-00-VP; Ad35 Env A; Ad5 Env A; Ad5 Env B I NCT01095224 VRC-HIVADV038-00-VP VRC-HIVADV014-00-VP; Ad5 env A, env B, env C, gag B, pol B; Ad5 Gag-Pol HVTN 084 I NCT01159990 VRC-HIVADV054-00-VP clade B VRC-HIVADV014-00-VP; VRC-HIVADV038-00-VP; Ad5 gag-pol/env A/B/C; Ad5 env A, Ad5 env B; HVTN 085 VRC-HIVADV052-00-VP; Ib NCT01479296 Ad5 env C; Ad5 gag-pol VRC-HIVADV054-00-VP; VRC-HIVADV053-00-VP Monitoring results: goals, strategic objectives and indicators page 183 ClinicalTrials.gov Trial Product Antigen Phase identier Viral vector - Adeno + Protein Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26. Ad26.Mos.HIV Trivalent; Mos2.Gag-Pol + Ad26.Mos.2.Env; Ad26.Mos.1.Env VAC89220HPX2004 II NCT02788045 Ad26.Mos4.HIV; gp140 DP + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol; protein gp140 C Ad26.Mos.HIV Trivalent; Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26. IPCAVD010 I NCT02685020 gp140 DP Mos2.Gag-Pol; clade C gp140 Viral vector - Pox + Protein ALVAC-HIV vCP1521; HVTN 097 Canarypox Env B,E; protein Env B,E I NCT02109354 AIDSVAX B/E ALVAC-HIV-C (vCP2438); Canarypox Env gp120 C, gp41 B, gag B., protease HVTN 100 Bivalent Subtype C gp120/ I/II NCT02404311 B; protein Env C MF59 ALVAC-HIV vCP1521; RV 305 Canarypox Env B,E; protein Env B,E II NCT01435135 AIDSVAX B/E ALVAC-HIV vCP1521; RV 306 Canarypox Env B,E; protein Env B,E II NCT01931358 AIDSVAX B/E ALVAC-HIV-C (vCP2438); HVTN 702 Canarypox Env gp120 C, gp41 B, gag B, protease B; Bivalent Subtype C gp120/ IIb *Scheduled protein Env C MF59 Viral vector - Adeno + Viral vector - Pox ChAdV63.HIVconsv; MVA. ChimpAd63 consensus; MVA consensus; PEACHI-04 I NCT02362217 HIVconsv AdCh3NSmut1; MVA-NSmut Viral vector - Adeno + Viral vector - Pox + Protein Ad26.Mos.HIV Trivalent; IPCAVD009 MVA Ad 26 mosaic; protein gp140 C I/II NCT02315703 gp140 DP; MVA mosaic Viral vector - Replicating IAVI R001 rcAd26.MOS1.HIVEnv Oral, replicating Ad26 mosiac Env I NCT02366013 PXVX-HIV-100-001 Ad4-EnvC150; Ad4-mgag Replicating Ad4 Env C; replicating Ad4 Gag I NCT01989533 Viral vector - Replicating + Protein Ad4-mgag ; Ad4-EnvC150; Replicating Ad4 Env C; replicating Ad4 Gag; HVTN 110 I NCT02771730 AIDSVAX B/E protein Env B,E Passive Immunization HVTN 704 AMP VRC-HIVMAB060-00-AB VRC01 antibody IIb NCT02716675 HVTN 703 AMP VRC-HIVMAB060-00-AB VRC01 antibody IIb NCT02568215 IMPAACT P1112 VRC-HIVMAB060-00-AB VRC01 antibody I NCT02256631 MB66-01 MB66 VRC01 antibody and HSV8 antibody I NCT02579083 VRC01LS VRCHIVMAB080-00-AB Modi"ed VRC01 antibody I NCT02599896 10-1074 10-1074 10-1074 antibody I NCT02511990 MCA-0835 3BNC117 3BNC117 antibody I NCT02018510 Source: IAVI’s Database of Preventative HIV Vaccine Candidates (8). page 184 Monitoring results: goals, strategic objectives and indicators References 1. 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Monitoring results: goals, strategic objectives and indicators page 185 Progress towards a universal in!uenza vaccine (Indicator SO6.2) Background In Currently approved vaccines and their limitations #ere are three broad classes of approved in of a novel pandemic strain of in General approaches to the development of universal in!uenza vaccines Numerous avenues are being explored to develop 1. Vaccines based on the conserved HA stem region. universal in 3. Vaccine design strategies using bioinformatics 7. Vaccines comprising a plurality of HAs from approaches to build consensus-based or optimized di&erent strains, intended to provide an antibody recombinant HA antigens in the form of proteins or response against the common determinants of the synthetic peptides. HA head. 4. Vaccines comprising nucleic acid coding for HA 8. Vaccines that combine multiple strategies, bringing followed by boosting with HA protein, intended together conserved regions from HA and internal to induce antibody response against the common proteins into a single vaccine. #ese multimeric determinants. DNA-based vaccines also include universal vaccines include virus-like particles, viral strategies designed to elicit host response against vectors or nanoparticle platforms. conserved internal proteins. 9. Testing vaccine combination modalities and prime- 5. LAIV that elicit a broadly cross-reactive, longer- boost approaches, including heterologous prime lasting host response. boost strategies. 6. Vaccines comprising conserved internal proteins such as the nucleoprotein or matrix protein, or fragments of these, in formulations destined to induce cell-mediated immunity. #ese include highly conserved peptide epitopes or expression of these internal proteins in viral vectors or nanoparticles. Opportunities and challenges Opportunities: Challenges: • Recent scienti"c "ndings on the role of broadly cross- • #e availability of a relatively e&ective annual in • Licensure of universal vaccines will require agreement • M2e-based vaccines such as M2e fused to TLR- on acceptable outcomes (prevention of infection or agonists (Vaxinnate). severe disease), e$cacy of these vaccines and the • Fusion proteins of multiple copies of the M2e region design of clinical trials and end-points. fused to the conserved nucleoprotein and conjugating to these immunostimmulatory oligonucleotides, such as being pursued by Dynavax. Current promising leads, strategies • Novel attenuated in Table 10.3: Development status of current vaccine candidates Organization Approach, target, adjuvant Phase I Phase II Licenced Phase III Preclinical Adjuvant MF59 allows for broader cross-reactivity against viral strains not XX included in the vaccine. Novartis (Switzerland) Synthetic, self-amplifying mRNA, delivered by a synthetic lipid nanoparticle X (SAM). GlaxoSmithKline (United Cross-clade antibody responses demonstrated with split-virion, inactivated, XX Kingdom) AS03-adjuvanted vaccine. Icahn School of Various approaches to target conserved broadly reactive epitopes on HA Medicine at Mount Sinai stalk, such as “headless” HA or functional chimeric HA (comprising non- (United States) and X matched “head” and “stalk”) expressed either in the context of whole virus GlaxoSmithKline (United or as rHA. Kingdom) Fusion protein between in Recombinant haemagglutinin (HA) expressed as virus-like particle (VLP) in Medicago (Canada) X tobacco plants. Requires adjuvant. Nasovax: Adenovirus 5, on PER.C6 cell line for vaccine production. X Altimmune (United States) Flunsyn. Former Immune Targeting Systems. Long peptides from four core X in Multimeric-001 vaccine: recombinant protein, combination of nine BiondVax conserved linear epitopes from HA, nucleoprotein (NP), and matrix protein X Pharmaceuticals (Israel) (M). SEEK (formerly PepTcell) Flu-v: mixture of four chemically synthesized peptides targeting conserved X (United Kingdom) T-cell epitopes present in M1, NP, and M2 (with oil-in-water adjuvant). Vivaldi Biosciences Replication-de"cient in Acambis Inc. (now Sano ACAM-FLU-A fusion between M2e and hepatitis B virus core protein X Pasteur) (France) (M2e-HBc) to produce VLPs presenting M2e. DNA plasmids encoding consensus sequences of HA, NA and NP delivered Inovio (United States) X by intradermal electroporation for eliciting antibody and T-cell responses. Fusion protein comprising two highly conserved in Antigen Express (United Synthetic peptides derived from conserved B cell epitopes from HA, linked X States) to MHC Class 2 Ii-Key moiety for facilitated # activity. PaxVax (Ad4 vector with PXVX0103 (Ad4-H5-Vtn administered as oral capsules) live adenoviral- X H5 HA) based vaccine against avian in Organization Approach, target, adjuvant Phase I Phase II Licenced Phase III Preclinical Orally delivered vectored vaccine. Non-replicating adenovirus type 5 vector Vaxart (hAd5 expressing backbone, which expresses HA from avian in Novel oil-in-water nano-emulsion that can incorporate, deliver and Nanobio (Nano-emulsion) adjuvant multiple antigen types, e&ective when administered via intranasal, X intramuscular or subcutaneous vaccination. Fusion protein between self-assembling ferritin protein and full length HA NAIAD (United States) X for nanoparticle presentation of HA. Janssen/Crucell Vaccine A stable trimeric in Replication-de"cient modi"ed vaccinia virus Ankara (MVA) expressing both NP and M1. Designed for strong cross-reactive T-cell response. Self- XX adjuvanted. Jenner Institute, University of Oxford Replication-de"cient simian adenovirus expressing both NP and M1. (United Kingdom) XX Designed for strong cross-reactive T-cell response. MVA expressing NP, M1 and conserved portion of HA. X Cytos Biotechnology M2 protein linked to a TLR7 ligand yielding high levels of IgG2c antibodies. X (Switzerland) Wistar Institute Fusion protein between M2e and NP, expressed in chimpanzee adenovirus X (United States) vector. Gamma Vaccines Whole virion gamma-irradiated virus for intranasal application. Elicits B X (Australia) and T-cell responses that are cross-protective. Self-adjuvanted. Sano Pasteur and VGTI VLP vaccine with computer-optimized consensus HA sequence (United Kingdom and (Computationally Optimized Broadly Reactive Antigen, COBRA). Elicits X United States) broad antibody response. Alum adjuvanted. Single-replication in University of Maryland, Rearranged genome of in Synthetic mRNA encoding HA and NP. Temperature-stable product, elicits CureVac (Germany) X both B and T-cell response. Self-adjuvanted. University of Adenovirus expressing broadly-neutralizing monoclonal antibody against Pennsylvania (United X HA delivered by intranasal administration. States) Georgia State University Multiple M2 extracellular domains expressed in a VLP. X (United States) Merck Research Synthetic peptides of M2 extracellular domain conjugated to keyhole limpet Laboratories X haemocyanin or Neisseria meningitidis outer membrane protein complex. (United States) Monitoring results: goals, strategic objectives and indicators page 191 Organization Approach, target, adjuvant Phase I Phase II Licenced Phase III Preclinical Bionor (Norway) Peptide-based approach targeting conserved epitopes (Vacc-Flu). X VBI (formerly Variation Unique technology using a mixture of eight to 32 peptides, which represent Biotechnologies) X hypervariable epitopes of HA to elicit polyclonal immune response. (United States) University of Wisconsin Modi"ed vaccinia virus Ankara encoding in Live attenuated in InvVax (United States) Linear invariable epitopes used to construct non-variable in University Of Utah Modi"ed HA sequence with mutations that reduce antigenicity of Research Foundation X immunodominant/variable epitopes. (United States) Okairos (Italy, Replication-defective pan adenovirus type 3 vector, expressing a fusion X Switzerland) protein of M1 and NP. University of Ghent (Vlaams Instituut voor Recombinant tetrameric protein, M2e-tGCN4 (modi"ed form of the leucine X Biotechnologie VIB) zipper of the yeast transcription factor GCN4 linked to M2e). (Belgium) University of Göteborg Fusion protein based on the CTA1-DD adjuvant and containing tandem X (Sweden) repeats of the M2e ectodomain epitope. Tsinghua University Synthetic peptide (N-terminus of M2e) coupled to carrier protein. X (China) University of Ottawa (Canada) and National Adenovirus vaccine encoding secreted fusion protein (codon-optimized X Institutes for Food and HA2 subunit fused to a trimerized form of murine CD40L). Drug Control (China) California Institute Adeno-associated viruses delivered intramuscularly, encoding two broadly- of Technology X neutralizing antibodies. (United States) Recombinant H7 haemagglutinin forms subviral particles that protect mice Medigen (United States) X and ferrets from challenge with H7N9 in KJ Biosciences M2e + fusion peptides X (United States) In References 1. Assessment of immune responses to H5N1 3. Evaluation of priming e&ects by pandemic live inactivated in Progress towards institutional and technical capacity to carry out vaccine clinical trials (Indicator SO6.3) Highlights • #e Eastern Mediterranean Region remains the followed by India. It is not certain that the trend region with the lowest number of clinical trials in China will continue, however. India has been overall and the highest number of countries with ranking consistently higher than any European no clinical trials occurring at all over a four- country over the four years of reporting. year period. • Caution is needed in interpreting these trends, as it • #e regions of the Americas, Europe and Western is not possible to determine whether they may be Paci"c report consistently high numbers of vaccine due partly or wholly to increased use of clinical trial clinical trials. However this hides substantial registries in countries. disparity between countries. • #ere continues to be a lack of adequate data- • China has become the country conducting the quality indicators that can be used at the second highest number of vaccine clinical trials global level. (due to a large increase in trials in 2015–2016), #e main changes in the landscape for clinical trial and other stakeholders. Other stakeholders (such as the activities are summarized below. National Institutes of Health, NIH) have also dra*ed guidelines on dissemination of results and data from In addition to a three-step process for all clinical trials, clinical trials, as well as forums and networks to increase WHO has advocated for the registry of all clinical trials clinical trial regulatory oversight and responsiveness, to prevent underreporting and ensure that the full extent particularly in developing countries. of data from such trials is accessible to Member States Data In order to ensure full comparability across the years of WHO region annually from 2012 to 2016 (using 1 May reporting all four years of vaccine clinical trial activity to 30 April as each 12-month period). #e results by has been provided for all Member States globally and by country and WHO region are presented in Table 10.4. Limitations of this indicator #e indicator for monitoring clinical research capacity the Netherlands National Trial Register, the Brazilian is the number of trials registered by country over Clinical Trials Registry, Clinical Trials Registry – India, a 12-month period. #is indicator is subject to the Clinical Research Information Service – Republic following limitations. of Korea, Cuban Public Registry of Clinical Trials, German Clinical Trials Register, Iranian Registry of • #e database searched is the WHO International Clinical Trials, Japan Primary Registries Network, Clinical Trials Registry Platform (ICTRP), which the Pan African Clinical Trial Registry, the Sri Lanka collates data from the following registries: the Clinical Trials Registry, and the #ai Clinical Trials Australian New Zealand Clinical Trials Registry, Register. Any clinical trials registered in other registries the Chinese Clinical Trial Registry, clinicaltrials. are not imported into ICTRP. gov, EU Clinical Trials Register, ISRCTN registry, page 194 Monitoring results: goals, strategic objectives and indicators • #e date used for classi"cation is the date of either with a later start date or it is possible some registration of the trial. #e date of registration may registries retroactively provide a date of registration not re WHO support to Member States and other developments in clinical trials capacity WHO has proposed a three-step process for all promoting dissemination of results of all NIH-funded clinical trials. clinical trials http://grants.nih.gov/clinicaltrials_fdaaa/. #e "nal new rules are awaited. • Step 1 is universal prospective clinical trial • In early 2016 the International Council of Medical registration using a registry compliant with WHO Journal Editors (ICMJE) conducted a public standards (www.who.int/ictrp). consultation on plans to mandate sharing of individual • Step 2 is public disclosure of results from the clinical participant data within six months of publication of trials within 12 months of the completion date for the all clinical trials in member medical journals going trial (http://www.who.int/ictrp/results/reporting/en/). forward http://www.icmje.org/news-and-editorials/ • Step 3 is consideration of sharing of the individual M15-2928-PAP.pdf. #e "nal ICMJE position on data participant data taking into account legal and ethical sharing is awaited. requirements. WHO does not mandate sharing individual participant data from clinical trials but notes In addition to this, important developments have taken that this is an area where policy is in the development place recently in addressing some of the challenges stage. WHO encourages that any sharing of individual posed by inadequate clinical trial regulatory oversight participant data should be conducted as a 3 rd step and responsiveness, particularly in Africa. #e African building on steps 1 and 2 . Vaccine Regulatory Forum (AVAREF) was formed in 2006 as a platform to build capacity for NRAs Further work by WHO and others regarding clinical and ethics committees, to promote harmonization trials policy is below. of requirements and practices and to reduce lengthy timelines associated with the review of clinical trials. • WHO published its institutional position on prompt Building upon earlier success, the AVAREF platform reporting of results from clinical trials in April proved critical in the joint and assisted Clinical Trial 2015 (http://www.who.int/ictrp/results/reporting/ Assessments (CTA) of candidate vaccines to combat en/), in addition to the Organization’s long standing EVD during the Ebola epidemic in West Africa in position that all clinical trials must be prospectively 2014–15. In an e&ort to further strengthen and expand registered (www.who.int/ictrp). AVAREF, an extraordinary meeting was held in Addis • Audits of the extent of clinical trial registration and Ababa 9–10 June 2016, resulting in a new vision, mission reporting are beginning to occur and be made available and governance structure with a steering committee (http://bmjopen.bmj.com/content/6/3/e009285.full and composed of heads of NRAs and national ethics http://bmjopen.bmj.com/content/5/11/e009758.full). committees. #e new Forum, whose scope has expanded #ese have shown that substantial non-reporting and to include medicines and diagnostics, is designed to even non-registration occurs and underpins major serve as a platform for joint reviews of multi-country biases in the evidence base. Action is needed by trials of vaccines and other technologies of public Member States to enforce dissemination of results from health interest, accelerate clinical review times, promote clinical trials. transparency and facilitate convergence based on the • In its o$cial Statement on Public Disclosure of African Medicines Regulatory Harmonization principles Clinical Trial Results, WHO has called on stakeholders of regional harmonization. AVAREF will also serve as in funding agencies, ethics committees, industry, the "rst pan-African regulatory network, providing academia, regulatory and publishing spheres to take a vehicle for product development partnerships and actions to ensure universal registration and reporting companies to discuss development plans and plan multi- of all clinical trials [REF]. Underreporting is equally country reviews. It is also expected to function as the high for industry sponsored or academic trials. precursor to the African Medicines Agency. • In 2015 the National Institutes of Health (NIH) conducted a public consultation on dra* new rules Monitoring results: goals, strategic objectives and indicators page 195 In parallel, the Developing Countries Vaccine prequali"ed vaccines, has already expanded its scope to Regulators Network (DCVRN), established in 2004 include product registration and vigilance. It is proposed as an international platform for strengthening the that DCVRN expand its responsibilities and activities regulatory oversight of vaccine trials, is also revisiting in a step-wise manner to include a broader range of its governance structure with a view to adopting a new medical products used for the diagnosis, prevention and operating model during an extraordinary meeting of treatment of infectious diseases that are endemic in, in November 2016. #e Network, composed of the and of interest to, developing countries. NRAs of developing countries that produce and export Table 10.4: Annuala vaccine clinical trial activity by Member State and WHO region, 2012–2016 b a) African Region Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Burkina Faso 3 0 1 2 Cameroon 0 0 0 1 Equatorial Guinea 0 0 1 0 Gabon 0 1 0 2 Gambia 0 3 1 1 Ghana 0 0 0 5 Guinea 0 0 1 0 Guinea-Bissau 1 0 0 0 Kenya 4 2 1 4 Malawi 0 0 1 3 Mali 0 1 2 5 Mozambique 1 1 0 2 Niger 0 0 1 0 Nigeria 0 1 0 3 Senegal 2 1 0 3 Sierra Leone 0 0 1 2 South Africa 11 14 3 7 Uganda 1 2 2 0 United Republic of Tanzania 1 3 0 1 Zambia 2 3 0 1 Zimbabwe 0 0 1 0 Total clinical trials 26 32 16 37 a Each 12-month period began on 1 May and ended on 30 April of the following year. b Data as of 30 June 2016. Note that the Comoros and San Marino could not be searched in the ICTRP database. page 196 Monitoring results: goals, strategic objectives and indicators b) Region of the Americas Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Argentina 5 1 3 1 Brazil 13 9 9 17 Canada 18 33 14 25 Chile 2 8 5 3 Colombia 6 14 10 8 Costa Rica 0 5 3 1 Cuba 4 4 3 8 Dominican Republic 5 5 5 4 Ecuador 1 0 0 0 Guatemala 2 2 1 0 Honduras 3 3 3 2 Mexico 9 5 11 11 Nicaragua 0 0 0 1 Panama 6 10 7 3 Paraguay 0 0 0 1 Peru 4 3 5 2 United States of America 108 120 101 100 Venezuela (Bolivarian Republic of) 1 1 0 0 Total clinical trials 187 223 180 187 c) South-East Asia Region Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Bangladesh 7 1 0 2 India 38 40 31 35 Indonesia 2 5 1 0 Sri Lanka 0 0 0 2 #ailand 16 13 11 19 Total clinical trials 63 62 44 58 Monitoring results: goals, strategic objectives and indicators page 197 d) Eastern Mediterranean Region Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Egypt 1 2 0 0 Iran (Islamic Republic of) 8 9 8 9 Jordan 1 0 0 0 Lebanon 1 1 0 0 Pakistan 4 2 0 0 Qatar 0 1 0 0 Saudi Arabia 1 1 0 0 Somalia 0 0 0 0 Sudan a 0 1 0 1 United Arab Emirates 1 0 0 0 Total clinical trials 17 17 8 10 a N.B. in the GVAP Secretariat report 2014 Sudan was listed under the African Region. e) European Region Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Austria 3 5 1 5 Belarus 0 0 1 0 Belgium 19 16 13 11 Bulgaria 2 1 1 2 Croatia 1 1 0 0 Czech Republic 18 9 8 9 Denmark 7 5 6 4 Estonia 11 5 3 8 Finland 19 13 8 13 France 10 15 7 12 Georgia 1 0 0 0 Germany 23 28 16 24 Greece 3 3 2 1 Hungary 6 6 4 3 Ireland 0 0 0 1 Israel 5 7 0 2 Italy 12 12 4 11 Latvia 0 0 2 2 Lithuania 1 1 2 3 page 198 Monitoring results: goals, strategic objectives and indicators Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Monaco 0 0 0 1 Netherlands 7 13 5 11 Norway 5 3 2 2 Poland 12 12 8 7 Romania 3 1 2 3 Russian Federation 10 10 6 4 Serbia 0 0 1 1 Slovakia 1 2 2 0 Spain 28 23 10 10 Sweden 14 9 4 12 Switzerland 3 4 5 4 Turkey 6 9 1 3 Ukraine 3 2 2 0 United Kingdom of Great Britain & Northern Ireland 31 36 19 25 Total clinical trials 264 251 145 194 f) Western Paci!c Region Number of trials Number of trials Number of trials Number of trials Country (2012–2013) (2013–2014) (2014– 2015) (2015–2016) Australia 32 29 25 22 Brunei Darussalam 0 0 0 0 Cambodia 0 0 0 0 China 29 28 30 50 Japan 6 13 5 12 Malaysia 6 6 3 0 New Zealand 8 6 3 3 Philippines 5 18 11 10 Republic of Korea 23 25 27 29 Singapore 3 4 5 4 Viet Nam 1 2 5 8 Total clinical trials 111 131 114 138 Monitoring results: goals, strategic objectives and indicators page 199 Licensure and launch of vaccine or vaccines against one or more major currently non-vaccine preventable diseases (Indicator G4.1) Licensure relates to registration by a functional national regulatory authority (NRA). Launch is de"ned as addition of the vaccine to the national immunization schedule in one or more low- or OPERATIONAL DEFINITION OF middle-income countries and sustained for a period of at least 12 months. Excludes use when INDICATOR limited to the private sector only. Includes vaccines in national schedule that may be selectively used in at-risk populations TARGET Progress towards licensure/launch of one or more such vaccines by 2020 DATA SOURCE/COLLECTION Subject matter experts; landscape reviews; clinical trial databases Incremental progress (i.e. number of products in phase I, II or III clinical trials) in development to MILESTONES be reported and assessed by SAGE Background Goal 4 of the Monitoring & Evaluation/Accountability CMV, RSV, group A streptococcus, leishmaniasis and Framework in the GVAP is to “develop and introduce helminth infections. To that end, the GVAP Secretariat new and improved vaccines and technologies”. Sub- consulted with experts, performed a landscape goal 4.1 speci"cally calls for an assessment of progress analysis and generated reports for each of the target towards licensure and launch of vaccine(s) against one diseases. #e selected candidate vaccines as a group or more major diseases, currently not preventable with were generally considered to provide a representative vaccines. #e current status of vaccine development indication of the changing state of the science. for HIV/AIDS, tuberculosis, malaria and a universal #e information below represents a high-level overview in Overview of current efforts In 2015, a live recombinant tetravalent vaccine against Table 10.5 shows the number of candidate vaccines dengue, Dengvaxia, designed for use in individuals for the seven target diseases currently in active clinical older than 9 years of age, was licensed in Mexico. Since development. As compared to 2014 more candidate that time, the vaccine has been licensed by NRAs vaccines are entering and progressing through the in other dengue-endemic countries. As discussed clinical development pipeline for "ve of the seven below, additional dengue candidate vaccines are target diseases. #ere are substantial basic research under development. and preclinical development e&orts in each of the target diseases. Current e&orts encompass a variety of diverse technologies and approaches, ranging from page 200 Monitoring results: goals, strategic objectives and indicators live attenuated (dengue, CMV, RSV) and inactivated developed for both prophylactic and therapeutic vaccines (dengue, RSV) to subunit-based vaccines indications (e.g. hepatitis C, schistosomiasis). (all target diseases). In addition, vaccines are being Table 10.5: Number of candidate vaccines against selected diseases currently in active clinical development a Target disease Phase I Phase II Phase III Dengue 4 1 2 Hepatitis C 3 1 0 Cytomegalovirus 12 6 1 Respiratory syncytial virus 11 2 2 Group A streptococcal disease 4 1 0 Leishmaniasis 2 0 0 Helminth diseases b 5c 0 1d a As of July 2016. b Includes schistosomiasis, hookworm, onchocerciasis and lymphatic filariasis. c Includes two candidate vaccines for Schistosoma mansoni infection and three for hookworm infection. d Includes one candidate (therapeutic) vaccine for Schistosoma haematobium. Opportunities and challenges Substantial opportunities for vaccine development for animal models for pathogenesis or protection; and the each of the target diseases derive from recent advances lack of correlates of protection/pathogenesis to help inter alia in genomic sequencing, proteomics, systems guide development. To address these questions, biology and structural biology, which are facilitating investigators are actively pursuing the development the identi"cation, credentialing and selection of of human challenge models for a number of diseases, candidate vaccines. In addition, increasing access to including notably dengue and hookworm. #e aim manufacturing capacity enhances process development of increasingly powerful analytical tools must be to and shortens the interval from preclinical concept detect and discriminate appropriate signals and identify to availability of clinical trial material. Furthermore, linkages to relevant biological e&ects. De"ning and technology is o&ering more and more tools for greater measuring crucial analytic characteristics for potency depth of analysis for characterization and quality and safety should be an important focus of future control of vaccines, and for characterization of relevant e&orts. Additional challenges relate to an incomplete immune responses. Priority lists produced by multiple understanding of the epidemiology of disease, organizations have renewed focus on development availability of and access to de"ned target populations e&orts for vaccines against diseases included in the with su$ciently high incidence rates to support e$cient GVAP. Public-private partnerships and advances in and cost-e&ective clinical trials, and a diversity of manufacturing processes provide promise that more clinical manifestations and outcomes depending on the cost-e&ective approaches toward vaccine development pathogens involved and the target populations. Vaccine may be realized. hesitancy and perceived safety concerns discourage enrolment and execution of clinical studies; a concerted, Interestingly, several common issues present challenges evidence-based e&ort will, therefore, likely also be to vaccine development for a number of the target required to address future delivery and deployment diseases, such as: an incomplete understanding of the issues. Finally, vaccine a&ordability should be considered pathogenesis (including immune-mediated disease at all stages of the development pathway without enhancement) and immunologically-mediated compromising quality standards. protection; the absence of adequate and/or predictive Monitoring results: goals, strategic objectives and indicators page 201 Current promising leads, strategies and technologies As noted above, numerous leads, strategies and can be important drivers, especially when identi"ed technologies are being pursued concurrently. early in the development cycle, that can support both #e candidate vaccines in phase III trials, representing innovation and subsequent access to a&ordable, high- the most advanced candidates, are based on recombinant quality products. Finally, investigators working at the live attenuated viruses (dengue vaccines), DNA vaccines basic and preclinical level of research for the targeted (human CMV vaccine), nanoparticles (RSV vaccines) vaccines as well as in phase I clinical trials are pursuing and adjuvanted recombinant proteins (schistosomiasis a variety of antigens, delivery systems and adjuvants to vaccine). Candidate vaccines in phase II trials are based elicit protective B- and T-cell responses. In addition, on live attenuated virus (RSV vaccine), recombinant it is worth noting that for zoonotic diseases such as live attenuated virus (dengue vaccine), viral-vectored leishmaniasis and schistosomiasis, veterinary vaccines vaccines (hepatitis C, CMV), DNA vaccines (human are also being pursued that may prove useful in future CMV), adjuvanted peptide combinations (Group control programmes and may serve as models for future A streptococcus vaccine), adjuvanted recombinant human vaccines for these diseases. Further details of proteins (human CMV vaccine) and subunit vaccines the various approaches being taken are discussed in the (RSV). Internationally-accepted quality standards references at the end of this section. Future directions A. Short-term goals (0–2 years) B. Medium-term goals (by 2020, end of the DoV) In the short term most e&orts in the seven target diseases are focused on maintaining momentum In the medium term e&orts are focused on post- and analysing ongoing projects. Of particular note licensure studies and delivery strategies, notably and interest, the recently licensed dengue vaccine regarding the licensed dengue vaccine. Support of will continue to be followed and where applicable, research and development to address unmet research the resulting analysis used to inform licensure of other opportunities and gaps identi"ed above remain high vaccines against dengue and the other target diseases. priorities as well as identifying promising vaccine Also, results from "ve phase III trials (for the tetravalent, candidates, developing and implementing the required live attenuated vaccines for dengue; the nanoparticle standards, and providing appropriate credentials to vaccines for RSV; and the adjuvanted, subunit vaccine advance their development as warranted. Assuming for Schistosoma haematobium infection) and a phase II encouraging results in phase I trials, a number trial of a hepatitis C vaccine are expected to be available of candidate vaccines will advance into phase II soon and will warrant careful analysis. In addition, trials. It is possible that vaccines to prevent human research and development e&orts will continue to CMV reactivation and RSV will be licensed in the address some of the research challenges identi"ed medium term. above, to prioritize standardization needs, and support advancement of promising candidate vaccines for all seven targeted diseases. C. Long-term goals (post-2020) In the long term the goals are to license safe, e&ective and a&ordable vaccines for all of the target diseases as needed to ful"l appropriate medical and public health mandates. page 202 Monitoring results: goals, strategic objectives and indicators Bibliography 1. Vannice KS, et al. Status of vaccine research and 6. Mo AX, et al. Visceral leishmaniasis control and development of vaccines for dengue. Vaccine. elimination: is there a role for vaccines in achieving 2016; 34(26):2934–2938. regional and global goals? Am J Trop Med Hyg. 2. Liang TJ. Current progress in development (in press). of hepatitis C virus vaccines. Nat Med. 2013; 7. Hotez PJ, et al. Advancing a vaccine to prevent 19 (7) 869–78. hookworm disease and anemia. Vaccine. 3. Krause PR, et al. Priorities for CMV vaccine 2016; 34(26):3001–3005. development. Vaccine. 2013; 32 (1):4–10. 8. Mo AX, Colley DG. Workshop report: 4. Higgins D, et al. Advances in RSV vaccine research schistosomiasis vaccine clinical development and and development – a global agenda. Vaccine. product characteristics. Vaccine. (in press). 2016; 34(26):2870–2875. 9. Cohen J. Un"lled vials. Science. 5. Steer AC, et al. Status of research and development 2016; 351(6268):16–19. of vaccines for Streptococcus pyogenes. Vaccine. 2016; 34(26):2953–2958. © PAHO/WHO © Monitoring results: goals, strategic objectives and indicators page 203 Licensure and launch of at least one platform delivery technology (Indicator G4.2) New platform delivery technology de"ned as a new mechanism for delivering vaccines to individuals that facilitates coverage, improves performance or reduces the cost of vaccine or DEFINITION OF INDICATOR delivery (e.g. jet injectors, microneedles, aerosols). Licensure relates to registration by a functional NRA. A launch is de"ned as the use of the technology in the national immunization programme of one or more low- or middle-income countries TARGET 2020: one or more vaccines DATA SOURCES Landscape reviews and meeting reports Background Innovations in delivery technology have many potential potent vaccine. Indeed, innovations such as auto-disable bene"ts. All are designed to increase access to life- syringes and vaccine vial monitors are now widely saving vaccines by improving deliverability and thereby used to improve the safety and e$ciency of vaccination accelerating uptake. Some platform technologies can programmes. New technologies on the horizon could help to facilitate outreach and increase vaccination lessen and simplify the workload of health care workers, coverage. Investment in new technologies can simplify which could further improve programme capacity delivery in routine immunization and campaigns, and impact. In addition, new delivery technologies helping to achieve the goal of reaching the one out of "ve can potentially increase e$cacy, reduce the amount children (the “"*h child”) who are missed by current of antigen required per dose, allow for vaccine immunization e&orts. Some can improve the safety of access during supply shortages and potential reduce vaccination programmes, for example, by reducing the total delivery cost by delivering antigens directly to risk of needle-stick injuries and preventing the re-use immunologically active tissues. of needles and syringes, or avoiding the use of non- Overview of current efforts Substantial progress has been made in advancing platform delivery technologies that have achieved or novel platform delivery technologies for vaccines, are advancing towards licensure and launch in low- and and this GVAP indicator is expected to be achieved middle-income countries within this time frame. by 2020. Table 10.6 summarizes a number of key Table 10.6: Summary of progress for key platform delivery technologies expected to achieve launch in low- and middle-income countries by 2020 Vaccine WHO Anticipated launch in Technology Manufacturer Licensure (NRA) application prequalication country Received USFDA Expected in 2017 Stratis 0.5 mL needle- 510(k) clearance in Clinical study (relabelling of Serum free jet injector July 2011 and approval PharmaJet complete with February 2013 Institute of India’s (subcutaneous and in August 2014 for MMR (1) MMR vaccine for intramuscular) delivery of A Tropis 0.1 mL needle- Intradermal CE mark received in Expected in Expected in 2017; free jet injector PharmaJet delivery of IPV June 2016 2016–17 by GPEI (intradermal) page 204 Monitoring results: goals, strategic objectives and indicators Vaccine WHO Anticipated launch in Technology Manufacturer Licensure (NRA) application prequalication country Helm/West USFDA clearance Intradermal Expected in Expected in 2017; Intradermal adapter Pharmaceutical received in February delivery of IPV 2016–17 by GPEI Services 2013 (3) Blow-"ll-seal primary Oral delivery of GlaxoSmithKline Expected in 2018 Expected in 2018 Expected in 2018 containers rotavirus vaccine Critical NRA approval in characteristics on Continued nationwide Multiple vaccine Barcodes All vaccines at least one LMIC secondary and expansions expected manufacturers expected by 2020 tertiary packaging in 2017 by 2020 Potentially all Vaccine vial monitor vaccines labelled with threshold Temptime for controlled NA Expected in 2016 TBD indicator (VVM/TI) temperature chain use USFDA, United States Food and Drug Administration; LMIC, low- and middle-income country. It is interesting to note that two of the platform delivery It is important to note that given the current supply technologies, the Tropis disposable-syringe jet injector shortages for yellow fever vaccine, fractional dose and Intradermal the intradermal adapter, are targeted subcutaneous delivery of this vaccine has also been for immediate availability in low- and middle-income recently recommended by WHO (6). Currently countries for polio outbreak control due to the limited WHO is procuring a new safety syringe with a "xed supply of IPV. #ese technologies o&er means for dose 0.1 ml dose and a suitable needle size and length for sparing (fractional dose) by delivering the vaccine subcutaneous delivery. intradermally resulting in adequate immune responses at lower doses. WHO has recommended that countries In the case of the PharmaJet Stratis, an MMR study consider intradermal delivery of fractional doses of conducted in India by the Serum Institute of India was IPV in the routine immunization schedule and these recently successfully completed which will ultimately devices are intended to enable that recommendation lead to relabelling of Serum Institute of India’s measles- (4). #ere are a number of studies supporting the use of containing vaccines for delivery with disposable-syringe such technologies delivering intradermal fractional dose jet injectors. Programmatic interest in using the Stratis IPV, which would facilitate the introduction of fractional has been expressed by MSF in particular, for measles dose of IPV (5). vaccine delivery, dependent upon the results of the Serum Institute of India MMR study. GPEI has recently "nalized purchasing agreements with PharmaJet and Helm/West Pharmaceutical Services Blow-"ll-seal is an alternative aseptic "ll/"nish for the Tropis and the intradermal adapter respectively process in which polymer containers are formed, for use in intradermal delivery of fractional dose IPV "lled, and sealed in a single operation. It o&ers an in support of polio eradication. #e initial purchase advanced degree of sterility assurance in comparison to orders comprise 4.1 million intradermal adapters with conventional "lling equipment, and has the potential to Helm autodisable syringes, 5000 Tropis devices and allow for comparable manufacturing costs to multidose 5 million needle-free Tropis syringes for use by Q1 vials but in multiple single-dose formulations. Blow-"ll- 2017. Launch of both technologies in low- and middle- seal also enables greater region in 2018 as well as through eventual UNICEF Bar code functionality was added to the logistics/vaccine procurement. Additionally it should be noted that information management system (OpenLMIS/VIMS) in Rommelag, a major blow-"ll-seal equipment company, the United Republic of Tanzania with an accompanying is developing a parenteral-capable blow-"ll-seal design guide describing how to recreate and reuse the barcode that is intended to meet the requirements for a compact library. Pakistan has built barcode functionality into pre"lled auto-disable device. their vaccine logistics management information system, and Ethiopia has similarly added it into their supply Barcodes represent a technology that has been broadly chain management system. Nicaragua extended the utilized in a number of "elds, to include assessment for pilot so*ware from the United Republic of Tanzania and use with vaccines. Improved supply chain and inventory replicated an end-to-end traceability test there. control has been demonstrated with this technology class. Currently barcodes are being utilized on a limited #e vaccine vial monitor with threshold indicator scale for vaccines and other health care commodities (VVM/TI) is being advanced as an option for the in a few low- and middle-income countries. To reduce monitoring of vaccines used in a CTC setting. the barriers to improved traceability, a multi-faceted #e VVM/TI will provide indication when the vaccine approach is being supported. #e United Republic has been exposed to a temperature higher than 40°C. of Tanzania, Pakistan, Ethiopia, and Nicaragua have #e interpretation of a VVM/TI is designed to be the all completed pilot projects of the use of barcodes on same as the current VVM; so additional training would secondary and tertiary packaging. #e United Republic not be required. To date, VVMs with separate prototype of Tanzania is completing a cost–bene"t analysis of threshold indicators have been used in CTC MenAfriVac barcode use to justify scaling the programme nationally. vaccine introductions. #e VVM/TI is currently Furthermore, Nigeria and the Democratic Republic undergoing WHO laboratory and "eld prequali"cation. of the Congo are making plans to require barcode Availability in low- and middle-income countries will labelling in the next few years. Work is also advancing be dependent on pricing, WHO recommendations/ to increase the availability of automated identi"cation requirements for use and demand from countries and data capture functionality within country systems. distributing vaccines in a CTC. Opportunities and challenges Over the past two years, there has been an increased the Gavi Alliance’s management board endorsed a new desire from manufacturers, policy-makers and strategic framework for 2016 to 2020, which expands procurement agencies for a tool that will enable Gavi’s strategic goal on market shaping to include evaluation of the trade-o&s between the impact that other immunization products in addition to vaccines. product innovation may have on vaccine development By working with other stakeholders in the market- cost, vaccine price and delivery cost. Such a tool would shaping community, the Gavi Alliance can help to facilitate the prioritization of public and private sector provide greater clari"cation and focus on promising investments in key platform and delivery technologies areas for product innovation with timelines beyond applied to speci"c vaccine products. WHO and PATH 2020, thereby informing strategic investment decisions are currently co-leading a delivery technology working in product development. group comprising subject matter experts from WHO IPAC member institutions, as well as representatives Work to advance barcodes on vaccine packaging has from the International Federation of Pharmaceutical bene"ted from the e&orts of a barcode WG formerly Manufacturers and Associations and the Developing under the Vaccine Presentation and Packaging Country Vaccine Manufacturer’s Network with a Advisory Group (VPPAG) and supported by GS1. mandate to provide guidance on new primary container Despite the expected bene"ts derived from barcode and delivery technologies, and to help inform how best technology, its path to adoption is hindered by a series to develop a tool to evaluate the potential programmatic of divergent standards for barcode use; and the need for utility and cost-e&ectiveness of these new innovations continued alignment of participants across the supply (see “future directions”). #e delivery technology WG chain ecosystem including WHO, UNICEF, vaccine reports directly to WHO’s IPAC. manufacturers, and countries. #e combined power of WHO prequali"cation activities, UNICEF purchasing In addition, concerted e&orts are being undertaken to coordination and manufacturer advancements in advance strategies that can serve to bring improved their packaging activities greatly accelerated the pace vaccine products to low- and middle-income countries and coverage of barcodes. However, the barcode WG for existing vaccines. For example, in December 2015, currently lacks involvement from WHO and UNICEF page 206 Monitoring results: goals, strategic objectives and indicators a*er reorganization of the VPPAG and may therefore to coordinate activities and share lessons learned; should disband. If this occurs, work to advance barcodes on this occur, it will set back the deployment of barcode vaccines will likely be ad hoc, without the opportunity capabilities within countries by several years. Current promising leads, strategies and technologies In addition to the key platform delivery technologies Novel primary containers are in development as well, (listed in Table 10.6), work is advancing on a number of which may reduce or simplify the storage and delivery other platform technologies – though these are unlikely of vaccines. #e blow-"ll-seal manufacturing process, to launch in low- and middle-income countries by 2020. which is being advanced for packaging oral vaccines, is also in development for delivery of parenteral Microarray patches (previously referred to as vaccines. Potential designs that are currently being microneedle patches) consist of an array of small evaluated for suitability include polymer blow-"ll-seal projections containing a dry formulation of a vaccine or vials, ampoules and compact pre"lled auto-disable pharmaceutical. When applied to the skin (like a plaster) devices. Other alternative primary containers which the vaccine dissolves into the upper layers of the skin. may be available in the future include integrated Potential advantages of this method of delivery include reconstitution technologies, in which the dry vaccine increased thermostability, ease of delivery, reduction in and diluent are packaged together or as an integral sharps waste, and the possibility of increased e$cacy or system and mixed within the device before delivery, dose sparing. #e development of microarray patches is potentially simplifying the logistics of transportation, a rapidly evolving "eld with upwards of 40 developers. the process of preparing vaccines and reducing the risks To date, microarray patches have been evaluated in of reconstitution errors that can result in adverse events clinical research for in References 1. ClinicalTrials.gov study number: NCT02253407. 6. Lower doses of yellow fever vaccine could be used Available at: https://clinicaltrials.gov/ct2/show/ in emergencies [website]. WHO statement 17 June NCT02253407?term=NCT02253407 2016 (http://www.who.int/mediacentre/news/ 2. FDA updated communication on use of jet injectors statements/2016/yellow-fever-vaccine/en/, accessed with inactivated in 9. Radius announces topline results of successful Phase 14. Edens C, Collins ML, Ayers J, Rota PA, Prausnitz 1b clinical trial of BA058 Microneedle Patch for the MR. Measles vaccination using a microneedle patch. transdermal treatment of osteoporosis [website]. Vaccine. 2013; 31 (34):3403–3409. Marketwired; 21 December 2011 (http://www. 15. Edens C, Collins ML, Goodson JL, Rota PA, marketwired.com/press-release/radius-announces- Prausnitz MR. A microneedle patch containing topline-results-successful-phase-1b-clinical-trial- measles vaccine is immunogenic in non-human ba058-1600924.htm, accessed 12 September 2016). primates. Vaccine. 2015; 33 (37):4712–4708. 10. ClinicalTrials.gov study number: NCT02438423. 16. Moon S, Wang Y, Edens C, Gentsch JR, Prausnitz Available at: https://clinicaltrials.gov/ct2/show/ MR, Jiang B. Dose sparing and enhanced study/NCT02438423 immunogenicity of inactivated rotavirus vaccine 11. Edens C, Dybdahl-Sissoko NC, Weldon WC, administered by skin vaccination using a Oberste MS, Prausnitz MR. Inactivated polio microneedle patch. Vaccine. 2013; 31 (34):3396– vaccination using a microneedle patch is 3402. immunogenic in the rhesus macaque. Vaccine. 17. Corbett HJ, Fernando GJ, Chen X, Frazer IH, 2015; 33(37):4683–4690. Kendall MA. Skin vaccination against cervical 12. Muller DA, Pearson FE, Fernando GJ, Agyei- cancer associated human papillomavirus with a Yeboah C, Owens NS, Corrie SR, et al. Inactivated novel micro-projection array in a mouse model. poliovirus type 2 vaccine delivered to rat skin via PLoS One. 2010; 4 (10):e13460. high density microprojection array elicits potent 18. Pearson FE, O’Mahony C, Moore AC, Hill AV. neutralising antibody responses. Sci Rep. 2016; 6: Induction of CD8 + T cell responses and protective pp 22094. e$cacy following microneedle-mediated delivery of 13. van der Maaden K, Sekerdag E, Schipper P, Kersten a live adenovirus-vectored malaria vaccine. Vaccine. G, Jiskoot W, Bouwstra J. Layer-by-layer assembly of 2015; 33(28):3248–3255. inactivated poliovirus and N-trimethyl chitosan on pH-sensitive microneedles for dermal vaccination. Langmuir. 2015; 31 (31):8654–8660. page 208 Monitoring results: goals, strategic objectives and indicators 2016 Global Vaccine and Immunization Research (GVIRF) Forum: Meeting Report Highlights • “Positive opinion” received from EMA under • Licensure of the "rst dengue vaccine has Article 58 for "rst anti-parasitic vaccine, RTS,S/ been achieved. AS01, to protect children from malaria. • Eb ola candidate vaccines have been developed with unprecedented speed through global collaboration. Introduction Research on the discovery, development and delivery of stakeholders in vaccine research and development. vaccines is an integral part of the GVAP and essential Leading scientists, vaccine developers and public health to achieving the vision of the DoV. WHO, the National o$cials from around the world discussed scienti"c and Institute of Allergy and Infectious Diseases (part of the technical challenges in identi"cation, credentialing and NIH) and BMGF convened the second GVIRF in March development of candidate vaccines, manufacturing and 2016. #is GVIRF aimed to track recent progress of regulatory issues and research to improve the impact of the GVAP research and development agenda, identify immunization. #is section summarizes the discussions opportunities and challenges, promote partnerships and conclusions from the forum participants. in vaccine research and facilitate the inclusion of all Progress and lessons learned Malaria vaccines Recent results from a large, multicentre phase III clinical trial of the most advanced candidate vaccine, RTS,S/ Re the in Immunization in the second year of life Regulatory authorities are responsible for protecting and beyond the public, including clinical trial subjects, from unsafe medical products while simultaneously facilitating the #e vaccine landscape has been exceptionally development and delivery of products with important dynamic in recent years, and several vaccines that public health bene"ts. In low-income countries, have entered public health programmes require regulatory bodies face many challenges, including additional immunization contact points. Similarly, weak capacity, poorly-de"ned processes and limited the immunization schedules of commodity vaccines pharmacovigilance. Manufacturers must grapple have been re-assessed. Implementation research to with disparate requirements and processes across assess the complexity of adding new immunization countries, a lack of guidance documents, inconsistent contact points is needed. Policies designed to introduce communication and poor transparency. AVAREF was vaccines into new age groups have not necessarily launched in 2006 to tackle these issues, by facilitating translated into changes in immunization practices and joint reviews with stringent regulatory authorities; have highlighted the complexities of adding a healthy supporting adoption of common application documents, child visit in the second year of life. #e challenges in approval guidelines and timelines; and promoting delivering MCV2 apply to other vaccination contacts for cross-learning. In the past decade reviews and children > 1 year old, including MenAfriVac (serogroup approvals of clinical trial applications for products A meningococcal vaccine), RTS,S, and other vaccines such as MenAfriVac, RTS,S, and TB vaccines have given to older age groups. Further research is needed to accelerated. AVAREF will be expanding its scope to clarify how to introduce a new visit successfully and use include medicines as well as vaccines and adopting a resources productively. regional approach. Progress toward measles control Regional vaccine manufacturing capacity and eradication Vaccine manufacturing capacity is unevenly distributed Even mature interventions and well-established control over the world. Today, Africa represents 14% of the strategies need regular scrutiny: progress, challenges world population (projected to increase to 25% in 2050), and opportunities were discussed for the measles and but has virtually no manufacturing capacity. Also, many African countries will be graduating from Gavi page 210 Monitoring results: goals, strategic objectives and indicators Alliance support over the coming years, thus increasing of emergencies and the recent attainment of disease demand for low cost, high-quality vaccines. control targets, are encouraging signs that overall #e African Union has taken steps to increase African vaccine acceptance is high. However, vaccine hesitancy pharmaceutical development and production capacity, has emerged in many communities and is having a with the dual goal of empowering African health systems profound impact on programme performance. Vaccine to respond to the health needs of their people, and to hesitancy is complex and context-speci"c, varying contribute to overall socioeconomic development. across time, place and vaccine. It includes factors such Following this lead, the African Vaccine Manufacturing as complacency, convenience, con"dence and trust. Initiative is expanding its pharmaceuticals strategy Addressing vaccine hesitancy requires an understanding to vaccines. of the magnitude and setting of the problem, diagnosis of the root causes, tailored evidence-based strategies to address the causes, impact evaluation to gauge if Vaccine demand and hesitancy the intervention has a&ected vaccine acceptance and ongoing monitoring. Comprehensive tools to assess and A cornerstone for increasing the impact of vaccines is address hesitancy have been developed and successfully acceptance of vaccination. #e overall high coverage used, with the promise that hesitancy can be addressed. rate of vaccination, the call for vaccines in the context Emerging technologies and insights Novel approaches to discovery vaccines for low-income countries. Such an approach and development has led to the development of malaria vaccines and MenAfriVac. #ese new vaccines must be designed with #e GVIRF provided a forum to illustrate a variety of delivery in resource-constrained environments in mind. novel approaches to better understand discovery and #is has led to a greater emphasis on preferred product development of vaccines. In recent years, a convergence characteristics and target product pro"les as a way to of advances in structural biology, molecular ensure user needs are factored into product development immunology and computational biology has created new decision-making. Although still a work in progress, total opportunities to design novel immunogens for vaccines systems e&ectiveness (TSE) represents the next step in against “hard-to-target” pathogens. Leading scientists this trajectory. TSE blends quantitative and qualitative presented studies showing how these approaches analysis of "ve factors in in nutritional uptake as well as control of in Persistent and new challenges Choosing intervention strategies and characteristics, which in turn can inform upstream vaccine targets research and development e&orts, and the utility of including a vaccine as part of an integrated disease In the initial plenary session recounting updates on control strategy. As was pointed out for TB, there may progress against HIV, malaria and TB, several themes be multiple outcomes of interest, e.g. prevention of in vaccine development were identi"ed that recurred in infection, prevention of primary disease or prevention other sessions throughout the GVIRF. #e "rst theme of recurrent disease. For malaria, outcomes of interest was the importance of identifying a speci"c target may include prevention of infection, prevention of indication for particular vaccines. Doing so informs disease and interruption or prevention of transmission. not only the clinical trial end-points, choice of assays Di&erent vaccines may be required to achieve these and go/no go criteria, but also the desired vaccine di&erent outcomes. With respect to HIV prevention, page 212 Monitoring results: goals, strategic objectives and indicators diverse interventions have already been identi"ed (e.g. antibiotics, pose major challenges to public health, adult male medical circumcision, treatment and pre- and raise expectations for vaccine-based interventions. exposure prophylaxis), and thus, as was demonstrated In response, WHO launched an e&ort to develop an in a recent modelling study, an opportunity exists to R&D Blueprint for priority diseases for which medical combine an HIV vaccine (even one with modest e$cacy countermeasures currently are lacking. #e development and modest population coverage) with these other and implementation of this roadmap will build on interventions to improve the overall rate of prevention. multiple partner e&orts. #e blueprint entails "ve workstreams, one of which is the prioritization of pathogens. Others address the development of Down-selecting among candidates platform technologies, research and development roadmaps, governance and coordination as well as Given the overall attrition rate in the vaccine "nancing options. development pipeline and the associated costs, the ability to down select e$ciently to choose the #e Ebola epidemic also revealed de"ciencies in most promising candidates for advancement was also regulatory preparedness. While many countries identi"ed as a recurrent theme. In some cases (e.g. TB) today have clinical trial legislation in place and follow standardized animal models are lacking or if available, International Council for Harmonization guidelines, have uncertain predictive power to identify candidates speci"c measures for public health emergencies are o*en likely to have the desired product characteristics in lacking. #ese are urgently needed to give regulators humans. In contrast, the use of human challenge models a framework within which to operate and convey employing well-characterized strains (e.g. for malaria) acceptable levels of More shots on goal Antimicrobial resistance Another recurring theme was the importance of As pointed out by speakers in a workshop at the GVIRF, maintaining a robust portfolio of vaccine candidates. the emergence and spread of antimicrobial resistance Given the attrition rates of candidate vaccines, (AMR) not only limits e&ective treatment options the probability of success in developing a vaccine for for signi"cant infectious diseases, but also imposes any given disease is likely to be greater if there are more substantial economic costs on health care systems. As a diverse candidates available for development. Advancing result, various public health agencies have developed candidates into clinical studies is an important step; comprehensive response strategies. Licensed vaccines when designed and conducted appropriately, clinical already play an important role by preventing both trials provide signi"cant learning opportunities to bacterial and viral illness that might otherwise lead to inform vaccine research and development, even when consumption of antibiotics. Presenters in the workshop a candidate may fail to achieve its original objectives. reviewed the current status of vaccine development If every candidate has to be taken completely through e&orts against methicillin-resistant Staphylococcus phase III trials, however, the costs can be prohibitive. aureus (MRSA) , antibiotic-resistant Neisseria #us, the importance of predictive preclinical or gonorrhoeae and hospital-acquired antibiotic-resistant early clinical studies to predict later stage success bacterial infections. In addition, considerable discussion becomes critical, and careful attention must be devoted took place in other sessions around other pathogens, to developing and validating such assays, systems such as Clostridium di"cile , X/MDR-TB and malaria. and models. A key message that emerged from these discussions was the important role that e&ective vaccines can play not only in preventing emergence but also spread Emerging infectious diseases of AMR, thereby preserving the current therapeutic armamentarium. Such vaccines would also be expected Over the past few years, emerging infectious disease to have substantial economic impact. For vaccines in threats have been a prominent theme on the global development, therefore, the threat posed by AMR for a public health agenda. #e epidemics of Ebola, Zika and given target disease may be an important consideration the growing threat from pathogens resistant to current in determining prioritization of e&ort. Monitoring results: goals, strategic objectives and indicators page 213 Conclusion At the midpoint of the DoV, much has remained But much has changed, and the value of vaccines has the same in vaccine research and development. never been more apparent. Polio is on the verge of We continue to see steady progress in the development eradication. Economic analysis has projected that and licensure of new vaccines, and continue to build each US dollar invested in vaccines in this decade expertise in designing and deploying innovative saves US$ 16 in treatment costs and productivity technologies for vaccine research, development and losses. When broader economic and social bene"ts delivery. Nevertheless, challenges persist: as noted are included, this rises to US$ 44 saved per US dollar above, HIV and TB vaccine development continues invested (1). Each emerging health threat, "rst Ebola to lag, and immunization rates still fall short, as each and then Zika, has triggered calls for new vaccines. year, 19.4 million children still do not receive the basic Innovation is needed to meet these challenges, vaccines they need. and to ensure that vaccines reach all those who need them most. References 1. Ozawa S, Clark S, Portnoy A, Grewal S, Brenzel L, Walker DG. Value of vaccines: return on investment from childhood immunization in low- and middle-income countries, 2011–20. Health A&airs. 2016; 35:2199–207.