Vaccination: Achievements, Challenges, Prospects Editorial

BULLETIN of the NETHERLANDS SOCIETY for TROPICAL MEDICINE and INTERNATIONAL HEALTH

N O 0 4 / d e c e m b e r 2 0 1 9 - v o l u m e 5 7

VACCINATION: ACHIEVEMENTS, CHALLENGES, PROSPECTS EDITORIAL

VACCINATION: ACHIEVEMENTS, CHALLENGES, PROSPECTS

he history of vaccination announced that type 3 poliovirus has is rich and full of success been eradicated worldwide. For polio to stories. It all started in 1768 be fully eradicated, all three wild polio when an English physi- strains (types 1, 2 and 3) need to stop cianT realised that prior infection with circulating. The three strains all cause CONTENT cowpox rendered a person immune to the same horrible symptoms, including smallpox. After several investigations paralysis and death, but are virologi- REVIEWS and tests in human beings in the years cally distinct. Type 2 was eradicated New developments in TB that followed, it was Edward Jenner, back in 2015; the last case of type 3 vaccine and correlate research another physician in England, who polio surfaced in northern Nigeria in offer real hope for better TB observed that milkmaids were generally 2012 and the virus hasn't been seen vaccines - 3 immune to smallpox. He postulated since. Today, only type 1 remains at that pus in the blisters that milkmaids large — in Afghanistan and Pakistan. Malaria vaccine development: developed from cowpox (a disease Enormous efforts are being made to silver bullet or shot in the dark? similar to smallpox, but much less finally eradicate polio completely. - 6 virulent) protected them from smallpox. In 1796, Jenner tested his hypothesis Many other diseases are being pre- Overcoming the challenges in by inoculating an eight-year-old boy: he vented through routine vaccination pro- achieving high immunization scraped pus from cowpox blisters on the grammes or through mass vaccination coverage in low-income hands of a milkmaid who had caught in the event of outbreaks. But there is a countries: the role of Gavi - 9 cowpox from a cow and inoculated whole series of conditions that deter- the boy in both arms that same day. mine the success of such efforts. In this The International Coordinating The boy developed a fever and some edition of MTb, you can read about vac- Group on Vaccine Provision - 11 uneasiness, but no full-blown infection. cination surveillance in the Netherlands The success of Jenner's discovery soon by our National Institute of Health and CALL FOR ARTICLES - 13 spread around Europe, with small pox the Environment (RIVM) – illustrated vaccination also being used for traders by the example of maternal pertussis Monitoring of vaccine in their expeditions to the Americas (whooping cough) which was added preventable diseases in the and the Far East. In 1980, following to the Dutch national immunisation Netherlands - 14 an historic global campaign of sur- programme in December 2019. The veillance and vaccination, the World media recently paid a lot of attention to Vaccine hesitancy: a new kid on Health Assembly declared smallpox reluctance among the general public in the block - 17 eradicated – the only infectious disease the Netherlands towards vaccination, so far to achieve this distinction. showing that high coverage rates are VIEWPOINT not to be taken for granted. Two articles Vaccination: who is best Polio (poliomyelitis) is another conta- in this edition reflect on what it takes equipped in the era of gious disease that could be eradicated, to safeguard high vaccination rates. postmodern mistrust? - 18 as there is an effective and inexpensive vaccine providing life-long immunity. Two other articles provide insight IN MEMORIAM - 20 The Polio Eradication Initiative is a UN into global mechanisms to ensure programme with the target of a polio- sustainable financing of vaccination free world. Initially experts believed programmes (the case of GAVI) and this could be achieved by the year reliable vaccine provision (the case of 2005, but that proved unrealistic. For ICG). The recent approval of an Ebola a region or continent to be certified as vaccine (November 2019) made news polio-free, there must be no detection headlines and several authors refer to it. of wild poliovirus for three consecu- If you are interested in the latest on vac- tive years as well as an appropriate cine development for TB and malaria, surveillance system. Recently, polio we recommend the first two articles got one step closer to becoming the of this edition. Enjoy the reading! second human disease to be fully wiped out. On 24 October 2019, World Polio Leon Bijlmakers, Jan Auke Dijkstra Day, the World Health Organization

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New developments in TB vaccine and correlate research offer real hope for better TB vaccines

Tuberculosis (TB) continues to tions (CMV, EBV) which can modu- Mycobacterium tuberculosis (Mtb) pro- pose an enormous threat to global late immune responses. As a result tein, called Ag85A, which was expressed health, with over one quarter of BCG vaccination has relatively little in a non-replicating viral vector (MVA) the world’s population latently impact on global TB transmission and had been designed as a booster infected, over 10 million new active patterns, which is a reason for TB vaccine for individuals that already have TB cases each year, over 1.3 mil- vaccine researchers and developers been given BCG. Although the vaccine lion annual deaths, and an ever- to promote TB vaccines that target was immunogenic and protective in cer- rising frequency of multi-resistant adolescent TB. tain animal models of TB, it was unable Mtb strains.[1] Classical intradermal to provide any additional protective M.bovis Bacillus Calmette-Guerin DEVELOPING NEW TB VACCINES efficacy against TB when administered (BCG) vaccination of neonates and Better TB vaccines could have sig- as a booster vaccine following BCG, in young infants protects against nificant impact against TB, and pre- a large phase 2b study in infants.[4] This severe forms of acute and early and post-exposure vaccination with disappointing result, which could have TB disease, with over 80% protec- improved vaccines represents a cor- been due to the fact that the Ag85A tive efficacy against TB meningitis, nerstone of the WHO End TB strategy antigen is insufficiently expressed by which can be rapidly fatal. Unfor- which aims to end TB by 2035.[1] To Mtb bacteria in the lung,[5] spurred addi- tunately, however, BCG vaccination discover and develop better TB vaccines, tional efforts to develop better vaccines. fails to protect consistently and research efforts were initiated in the sufficiently against pulmonary TB mid-1990s, sponsored both by private USING DIVERSE APPROACHES in adults, which is the main form of and public funding, particularly the ENHANCES CHANCE OF SUCCESS contagious TB.[2] The reasons for this European Commission.[3] Discovery and Five approaches have been actively deficiency are not fully understood evaluation of new candidate TB vaccines pursued in the last decade:[3] but may involve waning of memory, initially focused on the preclinical and interference by other infections early clinical space, from which emerged 1. Subunit vaccines which are based such as Non Tuberculous Mycobac- a first candidate, namely MVA85A. on specific immunogenic com- terial (NTM) or certain viral infec- This vaccine was based on a single ponents of the bacillus, such

Figure 1: Global Clinical Development of TB vaccines. (Reproduced from TBVI, see: https://www.tbvi.eu/what-we-do/pipeline-of-vaccines/)

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as proteins, fusion proteins two years after infection. The final had remained IGRA positive after and lipids, which are typically 3-year follow-up report was recently 24 months, representing a 45% VE admixed with innate immu- reported. Encouragingly, the vaccine signal. This finding could suggest that nity stimulating adjuvants; arm showed a 50% vaccine efficacy the immune system is able to eradi- against developing TB, although a cate an already established infection 2. Virally vectored subunit vac- relatively limited number of cases from the human body once properly cines in which the subunit was present in the control arm of this activated, in this case by revaccina- component is typically expressed large phase 2B trial. Nevertheless, tion. This interesting and important from a genetic insert encoding M72 has significant PoD VE, in the concept needs to be examined fur- a selected Mtb antigen (such as absence of major adverse effects. ther, including novel animal models, was the case for MVA85A); as it could focus research efforts on This encouraging result needs follow Mtb eradication by vaccination. 3. Improving BCG, by inserting up for longer periods of time in order to additional antigens or by genetic determine the longevity of the response, manipulation of the BCG genome and to assess whether further boost- UNDERSTANDING to improve its immunogenicity; ing would be required to maintain or augment the VE. At this stage, the THE IMMUNE 4. Attenuating Mtb by deleting mechanism of action of M72+AS01E MECHANISMS essential virulence genes, thus is unknown. It could involve innate producing a safe and antigenically immune driven responses, includ- BEHIND THE fully competent Mtb-like vaccine; ing trained innate immune memory PROTECTIVE of myeloid cells, and/or adaptive 5. Alternative delivery routes using immune responses (clear CD4+ T cell EFFECT existing vaccines, such as BCG, responses were induced by M72) or for example via the mucosal route both.[3,7] Understanding the immune (the lung) assuming that the mechanisms behind the protective NEW CLINICAL AND PROMISING natural route of infection is the effect will be important in order to LATE PRECLINICAL APPROACHES most relevant route of vaccine systematically improve and further There are, as already outlined in delivery, inducing local immunity develop this or other similar vaccines. Figure 1, several candidate vaccines in and immune (resident) memory. Besides determining the longevity of early stage clinical development. This the protective effect, another relevant includes live vaccines such as recom- RECENT SUCCESSES IN question is whether M72 also works well binant BCG and attenuated MTBVAC, TB VACCINE DEVELOPMENT in non-Mtb infected persons, includ- other subunit vaccines such as H56, Candidate vaccines from all five ing in BCG vaccinated individuals. and aerosol based delivery of BCG into categories are being evaluated for Notwithstanding these questions, this the human lung.[7] In parallel, advanced safety and immunogenicity in clinical landmark M72 trial result represents the preclinical evaluation models (usually in phase 1/2 studies, and some already first promising signal for any new TB non-human primates (NHP)) are being have been or are being evaluated in vaccine since a century, and now needs used to assess and compare additional phase 2B/3 studies for vaccine effi- to be evaluated in large phase 3 trials in TB vaccine delivery routes and systems. cacy (VE) using prevention of disease both infected and uninfected people. Some promising ones include: aerosol (PoD) or prevention of infection (PoI) / pulmonary delivery of BCG in NHP, as primary endpoints (Figure 1). A second promising result came from with excellent VE results;[9] intravenous a BCG revaccination study.[8] In this delivery of BCG (with strong VE results; Recently the results from two large stud- complex study design both a subunit Seder et al, unpublished), and Rhesus ies were reported, with highly encourag- (H4/IC31) and a BCG revaccination monkey-CMV vectored multi-antigen ing outcomes, strongly suggesting that arm were included in a setting in which subunit vaccines that are being tested better TB vaccines indeed are possible. (sustained) PoI rather than PoD was in NHP models, again with striking The most important results came from assessed. Infection was defined as VE effects.[10] In addition, combinato- a study in which a subunit vaccine (cat- having developed a positive immune rial vaccines with heterologous prime/ egory 1 above), called M72 test (IGRA test) against Mtb specific boost-regimens can likely be har- (a fusion protein consisting of 2 antigens. The most important result, nessed to further optimize protective immunogenic Mtb antigens), was which had not been anticipated, was immunity induced by vaccination. given together with a strong adjuvant, that although neither vaccine protected called AS01E, to adults who were against infection (i.e. IGRA conversion THE IMPORTANCE OF already latently (that is asymptom- from negative to positive) only BCG TB CORRELATES OF PROTECTION atically) infected with Mtb.[6] Most Mtb revaccination protected significantly ‘Correlates’, often referred to as ‘bio- infected people who will develop TB against sustained Mtb infection: in the markers’, are markers that correlate in their lifetime will do so in the first BCG revaccination arm fewer persons with important biological or medical

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In-Vivo Expressed Mycobacterium Tuberculosis outcomes, for example disease or protec- including multi-drug-resistant and Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine tion. Unfortunately, there are virtu- extensively drug resistant TB, and to Profiles. Scientific reports. 2016;6:37793. ally no human correlates of protection help reach the End TB goal by 2035.[1] 6. Tait DR, Hatherill M, Van Der Meeren O et al. Final analysis of a trial of M72/AS01E vaccine to prevent against TB. This is a major bottleneck Tuberculosis. New England J Med, 29th October 2019. 7. Andersen P, Scriba TJ. Moving tuberculo- delaying TB vaccine evaluation and sis vaccines from theory to practice. Nature prioritisation, because such corre- Tom H.M. Ottenhoff, MD, PhD Reviews Immunology. 2019;19(9):550-62. 8. Nemes E, Geldenhuys H, Rozot V et al. Prevention lates could help to identify protective Professor of Immunology, Head of Lab Dept of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. The New England antigens, develop improved vaccines, of Infectious Diseases, Head of Immunology journal of medicine. 2018;379(2):138-49. and allow the demonstration of immu- and Immunogenetics of Bacterial Infectious 9. Dijkman K, Sombroek CC, Vervenne RAW et al. Prevention of tuberculosis infection and dis- nogenicity and potential VE at an early Diseases Group, Leiden University Medical ease by local BCG in repeatedly exposed rhesus Center, Leiden, the Netherlands. macaques. Nature Medicine. 2019;25(2):255-62. stage. Correlates would thus facilitate 10. Hansen SG, Zak DE, Xu G et al. Prevention of the selection and prioritisation of can- [email protected] tuberculosis in rhesus macaques by a cytomegalovirus- based vaccine. Nature Medicine. 2018;24(2):130-43. didate TB vaccines for human clinical 11. Zak DE, Penn-Nicholson A, Scriba TJ et al. A blood RNA signature for tuberculosis disease risk: a prospec- efficacy testing, and help reduce the tive cohort study. Lancet 2016;387(10035):2312-22. protracted time scale, large size, and REFERENCES 12. Fletcher HA, Snowden MA, Landry B et al. T-cell activa- tion is an immune correlate of risk in BCG vaccinated expense of human efficacy trials, thus 1. WHO. Global Tuberculosis Report. 2019. infants. Nature Communications. 2016;7:11290. 2. Ottenhoff TH, Kaufmann SH. Vaccines against 13. Sloot R, Schim van der Loeff MF, van Zwet EW et significantly facilitating TB vaccine tuberculosis: where are we and where do we need al. Biomarkers can identify pulmonary Tuberculosis development. In addition, correlates to go? PLoS pathogens. 2012;8(5):e1002607. in HIV-infected drug users months prior to clini- 3. Kaufmann SHE, Dockrell HM, Drager N et al. cal diagnosis. EBioMedicine. 2015;2(2):172-9. could help guide preclinical animal TBVAC2020: Advancing Tuberculosis Vaccines 14. Suliman S, Luabeya AKK, Geldenhuys H et al. Dose from Discovery to Clinical Development. Optimization of H56:IC31 Vaccine for Tuberculosis- studies and thus help minimize use of Frontiers in immunology. 2017;8:1203. endemic populations. A double-blind, placebo- animals. Samples from well-defined 4. Tameris MD, Hatherill M, Landry BS et al. controlled, dose-selection trial. American J Respirat Safety and efficacy of MVA85A, a new tubercu- Critical Care Medicine. 2019;199(2):220-31. human cohorts with various Mtb losis vaccine, in infants previously vaccinated 15. Penn-Nicholson A, Hraha T, Thompson EG with BCG: a randomised, placebo-controlled et al. Correction: Discovery and validation of exposure or infection states, including phase 2b trial. Lancet 2013;381(9871):1021-8. a prognostic proteomic signature for tubercu- long-term resisters (either resisting 5. Coppola M, van Meijgaarden KE, Franken KL et losis progression: A prospective cohort study. al. New Genome-Wide Algorithm Identifies Novel PLoS Medicine. 2019;16(7):e1002880. natural infection induced IGRA conversion or resisting TB progression once infected), samples from future controlled human mycobacterial challenge SHUTTERSTOCK.COM models, and – particularly important – from individuals from trials with TB vaccines demonstrating protective VE will be essential for accelerating correlate discovery, testing and validation.

In addition, correlates of risk for progressing from asymptomatic (latent) infection towards TB disease would be extremely useful, e.g. in stratifying individuals in observational and clinical intervention studies, including (therapeutic) vaccination and drug studies. Several first signa- tures were reported a few years ago [11-13], and some of these are currently being further refined (e.g. [14,15]).

Although beyond the scope of this short review, it is clear that correlate discovery and evaluation is a second major priority in the field of TB vaccine development.

CONCLUDING FUTURE OUTLOOK In very recent years, TB vaccine research and TB correlate discovery have wit- nessed significant breakthroughs. This provides real hope for effective, life- saving TB vaccines, which are much needed to control the TB endemic,

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Malaria vaccine development: silver bullet or shot in the dark?

espite encouraging reduc- RTS,S AS01 (MOSQUIRIXTM) vaccine candidates. The first trials of tions in the global burden Development of RTS,S started in the RTS,S in African (Gambian) adults were of malaria in the early 21st late 1980s, following the discovery conducted around the millennium, century, progress has since that immune responses against P. but efficacy against naturally-acquired Dstagnated, particularly in the most Falciparum Circumsporozoite Protein infection proved somewhat disappoint- heavily affected areas of sub-Sa- (CSP) play an important role in pro- ing, protecting against only about 34% haran Africa. Implementation of an tection against infection. CSP is the of infections. Despite this setback, over effective malaria vaccine is con- most abundant protein on the surface the next decade further testing was sidered essential to bolster existing of sporozoites, the infectious form conducted in children and finally in tools (e.g., effective case manage- of the parasite transmitted by mos- infants, initially in Mozambique and ment, intermittent presumptive quitoes to people. The RTS,S vaccine subsequently in pivotal phase-3 trials treatment, seasonal malaria che- consists of recombinant (synthetically in several counties across sub-Saharan moprevention, and vector manage- produced) sections of CSP, fused and Africa. RTS,S has consistently demon- ment) and underpin control, or even combined with recombinant hepatitis B strated a good safety and tolerability perhaps for eradication of malaria. surface antigen (HBsAg). The addi- profile, but at ~18-36% protection against Ideally, a malaria vaccine would be tion of HBsAg helps to strengthen the episodes of clinical malaria, efficacy integrated into the World Health immune response against CSP, but remains well below the target threshold Organization’s (WHO) Expanded also induces potent immunity against of 75% set by the WHO.[1,2] Protection Programme of Immunisation, ben- hepatitis B virus. RTS,S is adminis- against severe malaria is lower still (1% efitting from the programme’s ex- tered in a strong adjuvant, AS01, to to 32%). A partial explanation for this isting management and logistics in further boost immune responses. relatively disappointing efficacy against order to effectively target those at naturally-acquired malaria infection greatest risk for malaria, i.e. infants Figure 1 summarises the developmental may be that the vaccine only protects and children. history of RTS,S, illustrating just how well against circulating P. falciparum So where are we currently in terms long such processes can take. Initial strains that genetically resemble the of malaria vaccine development – clinical testing was conducted in trials vaccine.[3] Moreover, protection is of do we have a silver bullet in hand, in malaria-naïve U.S. adult volunteers in relatively short duration, waning within or is it still just a ‘shot’ (of vac- the mid-90s, demonstrating safety and 3 years of initial immunisation. Indeed, cine) in the dark? After presenting protection against Controlled Human it has been suggested that RTS,S may some background, we will discuss Malaria Infections (CHMI). Such even cause a rebound-effect, whereby the current developmental status studies, in which subjects are deliber- susceptibility to malaria is increased in and prospects of three promising ately infected with laboratory-cultured the long term compared to unvaccinated examples of vaccines that target malaria parasites under highly con- subjects, at least in high-transmission Plasmodium falciparum, the most trolled conditions, have proven them- areas, due to slower induction of severe strain of malaria parasites selves an invaluable tool for advancing naturally-acquired immunity in vaccin- globally. the clinical development of promising ees.[4] In an attempt to overcome waning

Figure 1: Developmental history of RTS,S AS01 (MosquirixTM) vaccine. EMA – European Medicines Agency; GSK – GlaxoSmithKline; WRAIR – Walter Reed Army Institute of Research.

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immunity, a subset of participants in these trials are whether it is feasible and were first pioneered for malaria by the phase 3 trials were administered a logistically to target vaccine recipients Ruth and Victor Nussenzweig in the booster dose at 20 months after initial for a booster dose, and whether the 1960s and ‘70s.[6] Sporozoites can be immunisation; over 3-4 years of follow- marginally increased (but still extremely attenuated by radiation, genetic modifi- up, protection was indeed poorer in low) risk of cerebral malaria and menin- cation, or concomitant administration of subjects who did not receive a booster. gitis in children and a slight increase in chemoprophylaxis. The objective in all Importantly, protection is also relatively all-cause mortality in girls as observed cases is to ensure that these inoculated poorer in areas of high transmission, in RTS,S recipients in the phase 3 sporozoites abort their development and in infants as compared to children.[2] studies represent genuine associations before themselves becoming pathogenic or merely chance post-hoc findings.[5] blood-stage parasites; in the process Based on these results, in 2015 (some they are exposed to the immune system, 30 years since its first development) ATTENUATED WHOLE inducing protective immune responses RTS,S nevertheless received regulatory SPOROZOITE-BASED VACCINES against subsequent infections (Figure 2). approval from the European Medicines In an attempt to improve upon the Agency – the first malaria vaccine ever protection induced by RTS,S, other In a landmark study, researchers at to do so. Before taking a decision on researchers have been developing Radboud UMC (Nijmegen) pioneered whether to recommend the widescale second-generation vaccines consisting a highly efficacious form of immunisa- implementation of RTS,S, however, of attenuated live sporozoites. Live- tion known as ChemoProphylaxis-with- WHO has requested further large-scale attenuated vaccines are widely used Sporozoites (CPS), whereby subjects post-licensure trials. These commenced against other diseases (e.g., measles, are inoculated with infectious sporo- earlier this year in Ghana, Kenya and yellow fever and BCG for TBC) , are zoites by mosquito bites whilst tak- Malawi and will last until 2024. Some believed to induce stronger, broader ing anti-malarial prophylaxis (usually issues that remain to be resolved in and longer-lasting immune responses, chloroquine or mefloquine) to kill any parasites emerging from the liver into the blood-stream.[7] Alongside colleagues from Leiden UMC and Erasmus MC (Rotterdam), they have advanced this concept in a series of successful CHMI studies. This immunisation strategy, although not practically implementable on a large scale in resource-poor settings, remains the most potent known method for inducing immunity against malaria.[8]

The success of CPS has led to resurgent interest in the potential of attenuated whole-sporozoite vaccines. An important player in this field has been the U.S. biotech start- up Sanaria Inc., which pioneered a method to purify live aseptic P. falciparum sporozoites (PfSPZ) from the salivary glands of laboratory-reared mosquitoes and cryopreserve these in vials stored in liquid nitrogen. These can be shipped all over the world, thawed and administered intravenously by needle & syringe. This has helped to accelerate global vaccine development by allowing clinical trials to be conducted where they are most relevant, in resource- Figure 2: Life cycle of malaria parasites. Attenuated live sporozoites (white semicircles) abort their development poor settings in sub-Saharan before becoming pathogenic blood-stage parasites, in the process allowing the host to develop protective immune Africa. Indeed, Sanaria’s PfSPZ responses against subsequent infections. Irradiated sporozoites (e.g., PfSPZ Vaccine) arrest early during liver- stage development. In ChemoProphylaxis-with-Sporozoites (CPS), sporozoites complete liver-stage development Vaccine, consisting of radiation- but fail to multiply within red blood cells due to concomitant chemoprophylaxis. (Modified from Wikimedia attenuated sporozoites, has over Commons. Original source: National Institutes of Health.)

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the past decade undergone testing in this vaccine induced antibodies with African adults, children and infants potent ability to inhibit invasion.[11] Matthew B.B. McCall, MD, PhD, DTMH in amongst others Tanzania, Kenya, Clinical parasitologist, Department of Mali, Gabon and Equatorial Guinee.[9] In parallel with the clinical development Medical Microbiology, Radboudumc, of these vaccine strategies, state-of-the- Nijmegen, the Netherlands. Reminiscent of RTS,S however, protec- art technologies such as genetically- [email protected] tion in African populations, particularly attenuated parasite strains and passive infants, appears to be somewhat poorer immunisation with recombinant mono- Prof. Robert W. Sauerwein, MD, PhD than in malaria-naïve adult volunteers clonal antibodies are making inroads Clinical parasitologist, Department of exposed to CHMI in Europe and the in the P. falciparum vaccine field, with Medical Microbiology, Radboudumc, U.S. Potential explanations, including significant contributions from research- Nijmegen, the Netherlands. immaturity of young children’s immune ers in the Netherlands, and offer great systems, immunosuppressive effects of promise for the future. Moreover, vac- prior malaria exposure and/or helminth cines against the world’s second most REFERENCES co-infections, and parasite strain diver- dangerous malaria parasite, P. vivax, 1. Rts S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without sity, remain to be elucidated. Despite are also starting to be developed. a booster dose in infants and children in Africa: these set-backs, PfSPZ Vaccine is set to final results of a phase 3, individually randomised, controlled trial. Lancet. 2015;386(9988):31-45. undergo large-scale testing in a phase 3 Malaria vaccine development’s slow 2. Moorthy VS, Newman RD, Okwo-Bele J-M. Malaria vaccine technology road- trial in Equatorial Guinee later this year. track record, and particularly the rela- map. Lancet. 2013;382(9906):1700-1. tively disappointing efficacy of candidate 3. Neafsey DE, Juraska M, Bedford T et al. Genetic diversity and protective efficacy of the RTS,S/AS01 TRANSMISSION-BLOCKING VACCINES vaccines in naturally-exposed popula- malaria vaccine. N Engl J Med. 2015;373(21):2025-37. 4. Olotu A, Fegan G, Wambua J et al. Seven-Year Efficacy Vaccines targeting gametocytes (the tions, should of course caution against of RTS,S/AS01 malaria vaccine among young African parasite forms taken up by mosquitoes hubris. In parallel with empirical children. N Engl J Med. 2016;374(26):2519-29. 5. Guerra Mendoza Y, Garric E et al. Safety profile to complete malaria’s life cycle) can vaccine development, the field needs to of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III random- help to reduce transmission. Although develop a better understanding of funda- ized controlled trial in sub-Saharan Africa. Hum such a vaccine would not directly mental obstacles to malaria immunity, Vaccin Immunother. 2019;15(10):2386-98. 6. Nussenzweig RS, Vanderberg J, Most H et al. benefit its recipient, it could reduce including strain-diversity – currently a Protective immunity produced by the injec- tion of x-irradiated sporozoites of plasmodium cases of malaria in the community major area of research focus at amongst berghei. Nature. 1967;216(5111):160-2. and indirectly even the recipient’s others Radboud UMC. That said, ratio- 7. Roestenberg M, McCall M, Hopman J et al. Protection against a malaria challenge by sporozoite inocu- own chances of re-infection. Such an nal approaches and dedicated effort have lation. N Engl J Med. 2009;361(5):468-77. 8. Sauerwein RW, Bijker EM, Richie TL. Empowering altruistic vaccine could conceivably already advanced malaria vaccine devel- malaria vaccination by drug administration. be added to a multi-component vac- opment well beyond a proverbial shot in Curr Opin Immunol. 2010;22(3):367-73. 9. Richie TL, Billingsley PF, Sim BKL et al. Progress with cine that also induces direct protec- the dark. Several shiny-looking bullets Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines. Vaccine. 2015;33(52):7452-61. tion against infection or disease. look set to be added to our anti-malarial 10. Singh SK, Roeffen W, Andersen G et al. A Plasmodium arsenal and with concerted research falciparum 48/45 single epitope R0.6C subunit protein elicits high levels of transmission block- Several candidate vaccines induce one will yet be crafted of true ‘silver’. ing antibodies. Vaccine. 2015;33(16):1981-6. 11. Payne RO, Silk SE, Elias SC et al. Human vac- potent transmission-blocking immunity cination against RH5 induces neutralizing anti- in animal models and are currently malarial antibodies that inhibit RH5 invasion complex interactions. JCI Insight. 2017;2(21). undergoing clinical development. A WHO-INT leading example is Pfs48/45, a game- tocyte protein shown by researchers at Radboud UMC to form a critical link in mosquito-transmission. A recombinant vaccine, R0.6C, based on this protein is set to undergo testing here in first-in-human clinical trials in 2020, including assessment of transmission-blocking activity.[10]

PERSPECTIVES After years of largely unsuccessful attempts, exciting progress is now also being made towards a blood-stage malaria vaccine, based on reticulocyte- binding protein homolog 5 (RH5) that plays an essential role in the invasion of erythrocytes by P. falciparum merozoites. A first phase 1 trial of

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Overcoming the challenges in achieving high immunization coverage in low-income countries: the role of Gavi

hen Ebola hit West major investment from pharma developing countries. But even though Africa for the first time ceutical companies. a highly effective vaccine had been just five years ago, it available in wealthy countries since was a little known, but Its ability to clear these two hurdles 1982, only a minority of low-income muchW feared lethal disease. With no is in part due to the work of Gavi, the countries had so far introduced it. At the cure or vaccine available it could kill Vaccine Alliance based in Geneva, same time, global coverage of routine over 50% of people infected.[1] This, which seeks to increase access to new immunization was also plateauing, and the fact that people were unfa- and underused vaccines in low-income with more than 30 million children miliar with the disease and the way it countries. At the end of the West in the world’s poorest countries not spread, is why the disease was able to African outbreak, Gavi sent a signal being fully immunized even with the sweep across the region infecting more to the market that it would be there to basic vaccines. Gavi’s strategy was than 28,600 people and killing 11,300 purchase vaccines by committing to to bring together key players at the of them. Upon the recommendation make up to USD 345 million available global and local level – country govern- of the European Medicines Agency’s for Ebola vaccines. Then this particular ments, UN agencies, and civil society scientific committee to recommend vaccine was made available through organizations – to address the major the approval of conditional market an Advance Purchase Commitment mismatch between the people who had authorization for the world’s first agreement signed between Gavi and the access to vaccines and the people who Ebola vaccine (in October 2019), which vaccine manufacturer, Merck, in 2016. could benefit from them the most. By has been successfully deployed as an Gavi offered a USD 5 million pre-paid harnessing the financial resources and investigational product to fight the now commitment to Merck in exchange for expertise of these different partners, waning outbreak in the Democratic doses of the vaccine once it was licensed, Gavi aimed to increase the affordability Republic of the Congo, the World Health under the condition that Merck would and accessibility of life-saving vaccines. Organization formally announced its make a stockpile of investigational doses prequalification in mid-November. In available for outbreak response as well SUSTAINABILITY GOAL less than half a decade, Ebola has gone as some regulatory requirements. It is The most important partners within this from being nearly a death sentence these doses that have helped protect over Alliance are the implementing countries to a vaccine-preventable disease. 254,000 people against Ebola in DRC.[2] themselves. A cornerstone of the Gavi approach is that the organization works The significance of this is two-fold. This type of novel approach is indica- together with governments to build sys- Firstly, national regulatory bodies tive of the unique way that Gavi takes tems that they can sustainably finance can now choose to expedite their own on the challenges that exist in increas- well into the future, independently of approval for the ing access to vaccines. Since 2000, Gavi support. The Gavi model requires vaccine, just the Vaccine Alliance has been help- all countries, no matter how poor, to five years after ing protect some of the world’s most contribute some proportion of the cost of the West Africa vulnerable children against deadly the vaccines that they introduce through outbreak, whereas and debilitating diseases by leverag- Gavi. As a country’s economy grows, as the whole process ing innovative partnerships, technolo- measured by their gross national income can normally take gies, and financing mechanisms. per capita, so too does the proportion well over a decade. that they pay, until it reaches a point And secondly, it is GAVI’S INCEPTION of transition where the government a vaccine against In the late 1990s, new and under- has five years to fully fund its vaccine a disease that used vaccines were not reaching those programmes. So far, 15 countries have predominantly people most in need of them because transitioned out of Gavi support, with impacts some of new vaccines were made in low volume three more expected by the end of 2020. the poorest com- for high priced markets and therefore, munities in the most vaccines were simply not avail- THE MARKET SHAPING GOAL world: the type able at prices that their countries could Addressing the affordability side of vaccine that afford. For example, in 2000, hepatitis involves leveraging predictability would not tradi- B infections were killing more than of demand and economies of scale tionally attract 900,000 people a year, the majority in to secure lower vaccine prices. Gavi

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purchases vaccines for half of the IMPACT sub-nationally. This approach aims to world’s children and secures long-term Since 2000, Gavi has helped protect reach an additional 300 million children funding from donors, helping create the more than 760 million children with by 2025, saving up to 8 million more visibility of demand and reducing the vaccines against a range of diseases, lives. But also built into this plan is an risk of investment for manufacturers. and in doing so has prevented more understanding that many of the greatest This helps to incentivize manufacturers than 13 million deaths. Coverage with global health challenges we will face are to sustainably produce vaccines at prices the most basic vaccines has increased those that we cannot plan for. Climate that these countries can afford. And it from 59% to 81% in Gavi-supported change, antimicrobial resistance, and works. As of 2018, it cost only USD 27 countries.[4] This has paid dividends not emerging infectious diseases pose an to immunize a child with a full course just in terms of lives saved but also in ever-evolving risk. As the threats to of basic vaccines in a Gavi-eligible terms of helping to boost economies. our health become increasingly global- country, compared to USD 1,300 in In a Gavi-supported country, every dol- ized and increasingly unpredictable, the US. It has helped to build healthier lar invested in vaccines yields USD 54 the Vaccine Alliance provides a valu- vaccine markets serving low-income in wider societal benefits,[5] and since able opportunity to get a multitude of countries: the number of manufactur- 2000 this has translated into more than stakeholders around the same table. ers who supply Gavi with affordable USD 150 billion in economic gains. All This has already enabled Gavi to help vaccines has grown from five in 2000 this makes vaccines one of the most protect an entire generation of children. to seventeen today, now that there is cost-effective public health interventions Efficiency, innovation and collaboration a viable developing country market. ever. At the same time, vaccines bring will be the names of the game going for- us closer to the goal of Universal Health ward, to help us make further progress, Coverage, by acting as a platform that protect the next generation, and ensure EVERY DOLLAR helps to strengthen primary health care, that by 2030 no one is left behind. because vaccines don’t deliver them- INVESTED IN selves. With vaccination comes infra- VACCINES YIELDS structure, supply chains, cold storage Seth Berkley, MD USD 54 IN WIDER facilities, trained health care workers, Epidemiologist and CEO of Gavi, community outreach, data services, dis- the Vaccine Alliance. SOCIETAL BENEFITS ease surveillance, and much more. So, sberkley@gavi.org when communities get access to vaccination it puts these people on the map, and THE SYSTEMS GOAL it is often not long before they also get REFERENCES

Yet accessibility to vaccines relies not access to a host of other critical services. 1. Kucharski A, Edmunds J. Case fatality rates for Ebola virus disease in West Africa. Lancet just on the affordability of the vac- 2014; 384(9950):1260. Available from: https:// cines themselves, but on having strong GAVI 5.0 doi.org/10.1016/S0140-6736(14)61706-2 2. World Health Organization. Ebola virus dis- systems in place to deliver them. This is Ultimately, Gavi is built on the phi- ease Democratic Republic of the Congo: external situation report 68/2019. https://www.who. where local and private sector part- losophy that no-one should die of a int/publications-detail/ebola-virus-disease- ners play a crucial role in the work of vaccine-preventable disease, regard democratic-republic-of-congo-external-situation- report-68-2019. [Accessed November 26, 2019]. the Alliance. Worldwide, 19.4 million less of wealth, geography or gender. 3. World Health Organization. Immunization Coverage. https://www.who.int/news-room/fact-sheets/detail/ children are still missing out on some Yet every year 1.5 million people still immunization-coverage [Accessed October 27, 2019]. vaccines: many of them in remote rural do.[6] Reaching those still missing out 4. World Health Organization. Immunization, vaccines, and biologicals. https://www.who. communities, urban slums, displaced will prove increasingly challenging, int/immunization/monitoring_surveillance/ [3] data/en/ [Accessed October 27, 2019]. communities or areas of conflict. Gavi as population growth, rapid urbaniza- 5. ImmunizationEconomics.org. Decade of Vaccine works with the private sector to harness tion and climate change continuously Economics: return on investment. http://immunizationeconomics.org/dove-roi [Accessed October 27, 2019]. new technologies that can address these move the goalposts. As will the unprec- 6. World Health Organization. Immunization. https:// www.who.int/news-room/facts-in-pictures/detail/ bottlenecks. In Rwanda and Ghana, for edented migration we are seeing with immunization [Accessed October 27, 2019]. example, fleets of autonomous drones a record 70 million displaced people are now being routinely used to avoid recorded last year. That is why Gavi’s stockouts by delivering vaccines to new strategy, its fifth, covering strategic communities across both countries period from 2021-2025, called Gavi 5.0, SO FAR, when supplies are low or when there is prioritizing communities with zero is unexpected demand. Developed by dose children (children not received 15 COUNTRIES California-based technology company any routine vaccine doses) who have HAVE Zipline, and with support from the UPS historically missed out on vaccines. It Foundation and Gavi, these networks also recognizes the need to put gender TRANSITIONED are supporting millions of people, more at the centre of our programmatic OUT OF GAVI increasing the reach of health services planning, to ensure that communities and reducing waste at the same time. are engaged and to offer tailored support SUPPORT not just at the national level but also

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The International Coordinating Group on Vaccine Provision

accines are commodities BACKGROUND to pre-finance the purchase of vac- for which ordinary market Triggered by an outbreak of cerebro- cines, vaccine-related supplies, and mechanisms do not apply. spinal meningococcal meningitis antibiotics. Countries were expected to Their development includ- in in 1996 in West-Africa, the ICG reimburse the cost of vaccines drawn Ving clinical testing, the production was established as the International from the ICG stockpiles that were kept process, their shelf lives, and their Coordinating Group on Vaccine Provision by manufacturers in their warehouses often very limited supplier base, in for Epidemic Meningococcal Disease. to enable replenishment. In 2002, combination with unpredictable The outbreak affected primarily the Gavi Alliance (see the article on disease outbreaks and epidemics, Nigeria and Burkina Faso, with a total GAVI elsewhere in this edition) started regularly lead to vaccine shortages. of 152,813 confirmed cases and 15,783 providing financial support, initially It is good to realise that vaccines registered deaths. The actual incidence for the procurement of YF vaccine, later are a public good and access needs was probably considerably higher. also of Meningitis vaccines (2008) and to be equitable. From a public OCV (2013). At Gavi’s request, the ICG health point of view, national Since its establishment, the ICG has stopped the reimbursement require- health authorities and interna- undergone several changes. In 2001 ment for Gavi support-eligible countries tional development partners need to Yellow Fever (YF) vaccine was added in 2015. A year later, Gavi decided that ensure steady supplies and the effi- to its mandate, followed by Oral investments in emergency vaccine cient and fair distribution of scarce Cholera Vaccine (OCV) in 2013. The stockpiles would no longer be time- vaccines to places where they are ICG has three guiding principles:[1] bound and that non-Gavi-supported needed most. With new vaccines • Equity: distribution of vaccines countries were also eligible to access entering the market and many parts based on public health priorities; vaccines from the stockpiles, in the of the world in civil or military tur- • Rapid and timely access: deliv- understanding that they would ensure moil, where outbreaks and epidem- ery of vaccines within a defined replenishment, with Gavi covering the ics thrive, reliable mechanisms for timeframe to control outbreaks; financial risk in case they failed to do so. vaccine supply chain management • Independence: decisions made are of paramount importance. independently of political or The supply division of UNICEF plays a Vaccination is a main pillar in economic influences, with the sole key role in this process, as it procures emergency responses and dis- goal of improving public health. all the vaccines for the ICG stock- ease outbreak management while piles.[2] The revolving funds are now the vaccine market has gradu- Initially the ICG used a revolving fund dormant, leaving the Gavi Alliance ally become more complex. Ample supply is not a given anymore, e.g. only one manufacturer remains for the yellow fever vaccine. Ordinary lead times may be up to two years, shelf lives differ between different types of vaccines, and supply chain requirements have become more differentiated. Modern vaccines are very complicated in terms of production and quality control. As always, politics reign in this field as well, necessitating a fair public health approach which strives for equity and efficiency. This article describes the role of The International Coordinating Group on Vaccine Provision (ICG) in ensur- ing that scarce vaccines are available where they are needed as part of disease control.

SHUTTERSTOCK.COM / BY JOA SOUZA

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as the sole funding source for these financing, replenishment, monitoring, left the border area in DRC exposed to stockpiles. Gavi also provides fund- and reporting. In 2015, discussions further spread of the epidemic. The ing to support the operational costs started about an ICG mechanism for a criteria used during decision-making of emergency immunization cam- future Ebola vaccine.[3] An ICG Ebola differ among the three stockpiles paigns in Gavi-eligible countries. expert group is not in place though. because each outbreak has its own peculiarities. These criteria are publicly available. [4,5,6] The balance between responding to single outbreaks and

II considering the global epidemic context is and remains delicate. When R W I IRI working in epidemic or outbreak settings, public health experts should IR IE W EII I be aware of ICG’s existence and its modus operandi so they can act and

I RV advise in an appropriate manner.

THE GLOBAL DISEASE IE RREE CONTROL CONTEXT The occurrence of and response to I IE disease outbreaks need to be seen in the context of global disease control V RRIV strategies. In many cases outbreaks are E REIRE the consequence of insufficient coverage of routine immunisation systems and failure to compensate for that with effective special immunization Figure 1: The ICG mechanism (Adapted from: http://www.who.int/csr/disease/icg/qa/en/). activities, including campaigns. While ministries of health with the support of various partners usually implement The ICG Executive sub-Group is consti- The full ICG meets physically twice a control programmes for meningitis, YF tuted by its 4 founding members: WHO, year as well as through remote digital and cholera through routine preventive UNICEF-Headquarters, Médecins Sans conferencing in the event of an emer- and reactive immunisation, it is the ICG Frontières (MSF), and the International gency request. The ICG Secretariat that coordinates the management of Federation of Red Cross (IFRC). Other based at WHO-HQ plays a central and the three vaccine stockpiles, especially stakeholders, such as UNICEF’s Supply coordinating role in the entire ICG in emergency outbreak situations. Division (Copenhagen), Agence de mechanism. It also does price nego- Médecine Préventive (AMP), Centre tiations through its constituency and 1. CHOLERA for Disease Control, manufacturers, network, and evaluates interventions In 2013, WHO established the Global international NGOs, technical agen- and standard protocols for managing Oral Cholera Vaccine (OCV) stock- cies, financial partners and country vaccine-preventable diseases. Its infor- pile, and the Global Task Force on representatives (two from countries mality and flexibility is a key strength. Cholera Control (GTFCC) launched a in the African meningitis belt, plus a Vaccines are allocated based on techni- renewed strategy for cholera control in third country) support various activities cal and public health criteria without which OCV plays an important role. of the ICG mechanism, e.g. decision- political or financial considerations. [7] Many countries are now integrating making, forecasting of vaccine require- The ICG mechanism is depicted in the use of OCV within their cholera ments, procurement, and deployment. Figure 1. It aims at delivering vaccines control programs. As of May 2018, over The ICG Executive sub-Group reviews within a time span of a maximum of 25 million doses had been adminis- requests not only from countries but 10 days after receipt of the request. tered in 19 countries – of which 41% also from international organisa- in humanitarian situations, 38% for tions that act swiftly in the event of Recent major outbreaks – yellow fever outbreaks, and 21 % for endemic areas. disease outbreaks such as MSF. It can in DR Congo and Angola, cholera in do so within 48 hours after receipt by Yemen and the Horn of Africa – have 2. YELLOW FEVER its secretariat of a formal request. confirmed the need for effective man- The Yellow Fever Initiative was launched agement and distribution of vaccines in 2006 as a joint collaboration of WHO Standard operating procedures for of which the supply can be unreliable. and UNICEF. In 2016, a new more emergency stockpiles of meningitis In 2017 for example, the ICG had to specific and comprehensive strategic and YF vaccine (but not for OCV) are in prevent Angola from procuring large approach towards the Elimination place for vaccine applications, release, quantities of YF-vaccine that would have of Yellow fever Epidemics (EYE) was

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vaccines/Briefing_OCV_stockpile.pdf?ua=1 [8] developed. It involves a mechanism supply for some time, undermining the 7. https://www.who.int/cholera/task_force/en/ 8. https://www.who.int/csr/disease/yellowfev/ that automatically replenishes the emer- smooth implementation of the global eye-strategy-and-global-agendas/en/ gency stockpile to ensure that 6 million polio eradication strategy, it remains 9. Burki T. Ebola virus vaccine receives prequalification. Lancet 2019; 394(10212):1893. doses are available at all times. The ICG to be seen whether industry can meet https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32905-8/ remains responsible for rapid and inde- the future demand for Ebola vaccine. fulltext?dgcid=raven_jbs_etoc_email pendent decision-making on the alloca- tion of YF vaccines during emergencies. CONCLUSION Since infectious agents can spread faster 3. MENINGITIS than ever after an outbreak, even from There is no single strategy that com- very remote areas, vaccine-preventable bines prevention, routine immunisation, disease control is of global public health and emergency responses for meningi- importance. Both management and tis. At present the supply of serogroup financing of vaccine development and A meningococcal conjugate vaccine supply need to be secured through (MenAfriVac) is adequate and afford- close coordination of all stakeholders: able, which has helped substantially national authorities, international health to reduce the number and severity of organisations, international and national CALL meningitis outbreaks in countries of NGOs, and the vaccine manufacturing the African meningitis belt. However, industry. The ICG, with its secretariat meningitis outbreaks are now domi- based in WHO headquarters, plays a FOR nated by other meningococcal sero- key role in monitoring and guiding groups, for which conjugate vaccine vaccine provision. Its mandate and supplies are insufficient and expensive. capacity need to be safeguarded, free ARTICLES from any (geo)political interference. 4. EBOLA While comprehensive and adequate The recent approval of an Ebola vaccine mechanisms are in place for the three Following a request from following outbreaks in West-Africa vaccines discussed above that fall within several NVTG working parties and the eastern part of the Democratic ICG’s mandate, the recent approval of earlier this year, we hereby Republic of Congo (DRC) shows that an Ebola vaccine shows that there is call for contributions to next there is political will and funding to political will and funding to develop year's editions of MTb. The develop new vaccines in a much shorter new vaccines in a much shorter time Editorial Board is planning to time that ever before. An important that ever before. It is opportune to now cover the following themes: milestone in 2015 were the trials in also safeguard the provision of Ebola which more than 16,000 volunteers in vaccine. The ICG could fulfil that role. • Disease modelling Africa, Europe and the United States received the rVSV-ZEBOV vaccine. The Acknowledgement: This article is for a sub- • Mental health vaccine was found to be safe and to stantial part based on the report of an eval- offer protection against the Ebola virus. uation of the ICG in 2017 by a team from • Orphan diseases Following further testing during Ebola HERA-Belgium, of which the author was a outbreaks in DRC/Equateur province member. The author acknowledges the con- • Global Health education (in May-July 2018) and DRC/North Kivu tributions of fellow team members Dr. Josef province (still ongoing) and consulta- Decosas, Leen Jille and Marieke Devillé. • Support to church affiliated tions by the Strategic Advisory Group of hospitals in sub-Saharan Experts on Immunization (SAGE), the Africa: past and present Ebola vaccine was formally approved Henri van den Hombergh, MD, MPH and licensed by WHO in November Public Health consultant, the Netherlands. We would be pleased to receive 2019, just before this paper went to your contributions – in relation [email protected] press.[9] It means that the vaccine can to these themes or any other now widely be used, rather than under topic – in the form of an article, certain restrictions (‘expanded access’ REFERENCES news from the working party or what is also known as ‘compassion- 1. World Health Organization: Review of the in which you are involved, a International Coordinating Group on Vaccine ate use’). Ringfencing vaccination in Provision, 2006-2016. WHO Geneva, 2016 letter from the field, a personal combination with early case detection 2. www.https://www.unicef.org/supply/ viewpoint, or an ethical dilemma 3. International Coordinating Group for Ebola and widespread vaccination of health Vaccine, 1st Meeting, 11 December 2015 – WHO that you have come across. Headquarters, Geneva, Switzerland staff working in outbreak situations will 4. Meningitis guidelines: http://apps.who.int/ certainly boost demand. Considering iris/bitstream/10665/154595/1/WHO_HSE_ The Editorial Board GAR_ERI_2010.4_Rev1_eng.pdf?ua=1 the experience with bivalent polio 5. Yellow fever guidelines: http://www.who.int/csr/ disease/icg/ICG-request-form-EN.pdf?ua=1 vaccine, which was in short global 6. OCV guidelines: http://www.who.int/cholera/

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Monitoring of vaccine preventable diseases in the Netherlands The example of maternal pertussis vaccination

Pertussis, or whooping cough, is a was introduced following an advice VACCINATION UPTAKE bacterial infection of the respira- by the national health council in Vaccination coverage is assessed yearly tory tract. After the introduction of 2015, but it was not free of charge and reported in the annual vaccination mass vaccination in the 1950s, the and the vaccine has not always coverage report, using the individually bacteria seemed to have disap- been available. In December 2019, based vaccination registration system peared, but in the 1990s pertus- maternal pertussis vaccination will Praeventis.[6] After a small decrease sis re-emerged despite the high be added to the Dutch national im- in the period 2012-15, full vaccina- vaccination coverage rates, mostly munisation programme (NIP). tion coverage of 2-year old children affecting very young infants who The safety and effectiveness of all stabilized at around 90%. With the are not yet (fully) vaccinated (Figure vaccinations in the Netherlands, implementation of maternal pertus- 1).[1,2] In an effort to address this including maternal pertussis vac- sis vaccination, a new target group has problem, Tdap (tetanus, diphtheria cination, is monitored by the Centre been added to the NIP: all pregnant and acellular pertussis) vaccination for Infectious Disease Control (CIb, women are eligible and those who are for pregnant women, also called part of the National Institute of actually vaccinated under the pregnant the maternal pertussis vaccination, Health and the Environment (RIVM)) women (the enumerator) are regis- was introduced in the USA in 2011 together with the pharmacovigi- tered in the NIP register of Praeventis. and in England a year later.[3] Many lance centre Lareb. Surveillance of All pregnant women who deliver in a European countries followed soon diseases included in the NIP con- certain year in the Netherlands (the after that. By inducing the transfer sists of mandatory notifications and denominator) are registered in a special of antibodies from mother to child monitoring of laboratory and hos- perinatal register called Perined.[7] through the placenta, the vaccine pital admission data. Other ‘pillars’ provides protection of the new-born include vaccination uptake, adverse Acceptance of vaccination is periodically child until it gets its first vaccina- events surveillance, pathogen sur- assessed through qualitative studies.[4] A tion.[3] veillance and immunosurveillance recent study (unpublished), carried out The resurge of pertussis also hap- (Figure 2).[4,5] Here we illustrate in 2018-19 among pregnant women and pened in the Netherlands. Tdap these five pillars with the example mothers of children below the age of vaccination for pregnant women of maternal pertussis vaccination. two, assessed knowledge about maternal

Figure 1: Pertussis incidence in the Netherlands stratified by age group, 1999-2018.

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Figure 2: Five pillars of NIP surveillance in the Netherlands.[5] pertussis vaccination and willingness reviews show that maternal pertussis developed by Farrington.[12] For the to vaccinate. It showed that 70% of the vaccination is safe. No adverse preg- calculation of the VE of maternal women had heard or read about mater- nancy outcomes, such as stillbirth or pertussis vaccination, the coverage nal pertussis vaccination, and 60% neonatal death were reported.[3,8-10] After of a certain age cohort and the differ- of pregnant women had the intention implementation of maternal pertussis ence in pertussis incidence between to get vaccinated. The most common vaccination, safety monitoring will also vaccinated and unvaccinated children reason among women who had already be performed in the Netherlands to pro- below 3 months of age is needed. given birth to refrain from vaccination vide relevant information to the public. was lack of information: when they were pregnant they did not know that this was DISEASE SURVEILLANCE THE MATERNAL an option. Most pregnant women inter- Besides monitoring of hospital admis- PERTUSSIS viewed indicated a high level of trust in sions and mortality attributed to the information provided by their mid- vaccine-preventable diseases, disease VACCINATION wives, consultation centres and RIVM surveillance involves mandatory notifi- (78%, 70% and 79%, respectively). cations. WHO also requires notification WILL BE (annually), and there is an exchange of IMPLEMENTED IN SAFETY SURVEILLANCE information on the occurrence of several Safety surveillance is important to diseases (e.g. diphtheria, tetanus, polio- THE NETHERLANDS assess the nature and frequency of myelitis, pertussis, mumps, measles, BECAUSE OF adverse events in order to ensure the rubella, hepatitis B, and meningococcal population does not mistrust the NIP. disease) with other European countries THE HIGH This pillar relies on a passive report- through the European Surveillance INCIDENCE OF ing system of adverse events following System (TESSy) of the European immunisation (AEFI), in place at the Centre for Disease Control (ECDC). PERTUSSIS centre for pharmacovigilance in the [11] Differences in incidence between IN NEW-BORN Netherlands, Lareb. Both professionals countries, considering their vaccination CHILDREN and the general public can report AEFIs. programme and history, are evalu- It is important to bear in mind that ated to optimize vaccination impact reported events do not necessarily have a and better identify high-risk groups. (proven) causal link to vaccination. The PATHOGEN SURVEILLANCE influence of media attention on such The maternal pertussis vaccination will RIVM studies the possible adaptation of reporting should not be underestimated. be implemented in the Netherlands the Bordetella pertussis bacteria based on When notable signals are observed, because of the high incidence of per- samples provided by medical microbi- Lareb performs a causality assess- tussis in new-born children (Figure ology laboratories. It involves antigen ment and decides what is more likely: a 1) combined with a good vaccine expression validation assays to deter- causal relation with the vaccination or a effectiveness. Vaccine effectiveness mine pertussis antigens: pertussis toxin coincidental signal. Regarding maternal (VE) in the Netherlands is usually (Ptx), pertactin (Prn), and filamentous pertussis vaccination, safety studies and assessed through a screening method hemagglutinin (FHA). A high frequency

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of pathogens that are deficient in one FUTURE PERSPECTIVE REFERENCES of these genes could predict vaccine Given the rapid development of new vac- 1. Van der Maas NA, Mooi FR, de Greeff SC et al. Pertussis in the Netherlands, is the current vac- evasion, which might lead to a pertus- cines, the ever-changing epidemiology cination strategy sufficient to reduce disease burden sis outbreak.[4] Recently, whole genome of vaccine preventable diseases, and new in young infants? Vaccine. 2013;31(41):4541-7. 2. Mooi FR, Van Der Maas NA, De Melker HEJE. sequencing was introduced, which can scientific evidence that has implica- Infection. Pertussis resurgence: waning immunity and pathogen adaptation–two sides of detect even smaller strain differences tions (e.g. for vaccination schedules), the same coin. 2014;142(4):685-94. and changes. A change in the pertussis close monitoring of NIP performance 3. Gkentzi D, Katsakiori P, Marangos M et al. Maternal vaccination against pertussis: a sys- strains due to the maternal pertussis is crucial. When a new vaccination is tematic review of the recent literature. Arch Dis Child Fetal Neonatal Ed. 2017;102(5):F456-F63. vaccination is not expected, as the vacci- introduced, RIVM takes charge of the 4. RIVM. The National Immunisation Programme nation protects against the same strains necessary surveillance. With the five in the Netherlands: Surveillance and developments in 2016-2017. National Institute for as the vaccination during childhood. pillars of the Dutch surveillance system Public Health and the Environment; 2017. 5. Van der Maas NA. Vaccine-preventable diseases: evalu- in place, all elements of surveillance of ation of vaccination programmes and optimisation of IMMUNOSURVEILLANCE vaccine preventable diseases are covered, surveillance. Zeist, The Netherlands 2018. 16-8 p. 6. RIVM. Vaccinatiegraad en jaarverslag Protection against disease can be safety and effectiveness are closely Rijksvaccinatieprogramma Nederland 2018. Rijksinstituut voor Volksgezondheid en Milieu; 2019. assessed by measuring antibody levels monitored, and cross-border communi- 7. Perined. Perinatale Zorg in Nederland (seroprevalence). Seroprevalence studies cation and data-sharing is happening. 2017. Utrecht: Perined; 2019. 8. Donegan K, King B, Bryan PJB. Safety of per- enable the identification of susceptible tussis vaccination in pregnant women in UK: observational study. BMJ 2014;349:g4219. population groups that are at risk of 9. Munoz FM, Bond NH, Maccato M et al. Safety infection, and provide a standard- J. Fröberg, MSc and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during ized value to compare countries. N.A.T. van der Maas, MD, PhD pregnancy in mothers and infants: a random- Serosurveillance in the Netherlands, ized clinical trial. JAMA. 2014;311(17):1760-9. H.E. de Melker, PhD 10. Campbell H, Gupta S, Dolan GP et al. Review of vac- also called immunosurveillance, is done cination in pregnancy to prevent pertussis in early Epidemiology and Surveillance, Centre infancy. J Med Microbiol. 2018;67(10):1426-56. by the RIVM/CIb. They periodically 11. for Infectious Disease Control, National Surveillance atlas of infectious diseases ECDC: ECDC; collect blood samples and demographic 2017 [Available from: https://www.ecdc.europa. Institute for Public Health and the eu/en/surveillance-atlas-infectious-diseases. data from a representative sample. 12. Farrington CP. Estimation of vaccine effectiveness using Environment, Bilthoven, the Netherlands. the screening method. Int J Epid. 1993;22(4):742-6. 13. Barug D, Pronk I, van Houten MA et al. Maternal [email protected] pertussis vaccination and its effects on the immune The immunologic effects of the mater- response of infants aged up to 12 months in the nal pertussis vaccination were measured Netherlands: an open-label, parallel, randomised controlled trial. Lancet Infect Dis. 2019;19(4):392-401. in the Maternal Immunisation Pertussis 14. Maertens K, Caboré RN, Huygen K et al. Pertussis vaccination during pregnancy in (MIKI) study at the RIVM/CIb, which Belgium: results of a prospective controlled concluded that infants of women who cohort study. Vaccine. 2016;34(1):142-50. 15. Becker-Dreps S, Butler AM, McGrath LJ et al. obtained maternal pertussis vaccina- Effectiveness of prenatal tetanus, diphtheria, acellular pertussis vaccination in the prevention of infant pertus- tion could be vaccinated twice, at 3 and sis in the U.S. Am J Prev Med. 2018;55(2):159-66. 5 months, instead of three times (at 2, 3 and 4 months).[13] The Premature Infants and Maternal Pertussis Immunisation (PIMPI) study, also conducted by RIVM/ CIb, assesses the immunologic effects of maternal pertussis vaccination in premature infants, and the effect that timing of this vaccination has on antibody transmission from mother to child. Research on the immunologic effect of maternal pertussis vaccination in other countries has shown an increase in antibody levels during the first months of life in children whose mother had been vaccinated. Furthermore, several studies reported a lower immune response after the first dose of infant vaccination when the mother had been vaccinated during pregnancy. This is called ‘blunting’.[10,14] Recent research has shown no clinical relevance for the blunting effect, and confirmed that FULL VACCINATION COVERAGE OF 2-YEAR maternal pertussis vaccination offers OLD CHILDREN STABILIZED AT AROUND 90% protection against pertussis.[10,15]

16 MT BULLETIN OF NVTG 2019 DECEMBER 04 REVIEW

Vaccine hesitancy: a new kid on the block

accination is one of the vulnerabilities. But there are also A MORE SYSTEMATIC APPROACH most effective public issues of communication and de- TO COMPREHENSIVE VACCINATION health interventions, liberate attempts to undermine the PROGRAMME DEVELOPMENT and one that prevents success of vaccination by so-called Until recently, most vaccination 2-3 million deaths ´anti-vaxxers´. They spread and take programmes had an information and worldwide every year.[1] advantage of public fears about the education component, using various VIn 2018, 86% of all eligible infants safety of vaccination. How to deal channels (individual letters, posters, in the world received at least one with these challenges? group meetings, etc.), and they offered dose of measles vaccine and 69% various service options (e.g. vaccina- received the second dose, leaving tion on appointment). With the advent around 20 million children who did THE QUESTION of the internet, this appears to be no not receive any dose. Also about IS: HOW DO longer sufficient. A modern success- 86% of infants worldwide (116.3 ful vaccination programme needs to be million infants) received their PEOPLE based on a good understanding of the third dose of diphtheria-tetanus- MAKE THEIR enablers and the barriers to vaccina- pertussis (DTP), with 129 countries tion acceptance and include an effec- achieving at least 90% coverage DECISIONS? tive translation of behavioural change [2] These are tremendous achieve- methods into practice. Careful planning ments. However the health gains with relevant stakeholders in various achieved by the success of vaccina- BETTER UNDERSTANDING OF stages of a vaccination programme is a tion programmes are under threat. DETERMINANTS OF must. It starts with answering ques- The rise in the incidence of measles, VACCINATION ACCEPTANCE tions such as ‘What is the problem?’ and especially observed in Europe People feel the need to make an ‘For whom is this a problem?’, followed and North America, the 2015-16 informed and deliberate decision pro by the question ‘Which determinants outbreak of yellow fever in Angola, or contra vaccination for themselves could influence vaccination acceptance?’ and two new cases of polio in the or their children, but they often feel Subsequently, it is important to discuss Philippines can be directly linked unable to do so based on the available how to achieve the programme goal by to a decrease in vaccine coverage information. Information provided by answering a question like ‘Who has to in these countries. They illustrate health authorities is perceived as too do what in order to promote vaccination the challenges we face in protect- limited or biased. Information available under the target group?’ Next, the most ing citizens against the threat of on the internet is often unbalanced and relevant and amenable determinants vaccine-preventable diseases. There does not give the full picture. Parents of have to be selected. In the third step, a is a tendency for people to delay in young children do not always consider strategy can be designed by arranging accepting or even refusing vac- the information provided by health all change objectives by determinant cination altogether, despite the professionals as satisfactory, with some and identifying theoretical methods widespread availability of vac- arguing that it is not designed to inform which are potentially applicable for cination services. This is referred but to induce conformity. Other factors that determinant in order to achieve to as vaccine hesitancy. The most that play a role for people to accept or the change objective. Feasibility and important determinants are indi- refuse vaccination include personal possible fit of the practical applications vidual choices and group influences, convictions, for instance after some of these methods with the needs and combined with specific features of bad experience with vaccination or a intervention context of the target group certain vaccines and vaccination- disease, psychosocial determinants are essential. Integration of the various related issues and often aggravated (e.g. risk perception, feelings of loss elements that were chosen in the previ- by contextual factors.[3] of control, or decisional uncertainty), ous step will lead to a concrete approach and pragmatic reasons (e.g. time containing, for instance, a personal Maintaining high vaccination cover- constraints, inconvenient location, or invitation letter, an information folder age levels to protect the population limited provider choice). So the ques- or website, and a deliberation tool.[3] requires a permanent commitment tion is: ‘How do people make their by those delivering, monitoring, and decisions on whether or not to accept Once a vaccination programme has funding vaccination programmes. specific vaccinations?’ While there is an been developed, implementation must Poor vaccination uptake may reflect abundance of literature on how people guarantee improved access to vaccina- changing societies with shifting make personal choices in their lives, tion and provide different sectors of values and preferences, greater little research has been conducted on the healthcare workforce with adequate mobility of people, and changing decision making regarding vaccination. resources. They must be able to deliver

DECEMBER 04 2019 MT BULLETIN OF NVTG 17 REVIEW

a high-quality vaccination programme that develops data solutions to enable Vaccination: who is best individuals to demonstrate their vaccination status regardless of where equipped in the era of they are and that provides clear mes- sages on the evidence for vaccination. postmodern mistrust? Vaccination programme monitoring must also help to identify groups and communities that are most under- Public health is a science and profession with an im- served in order to vaccinate them. pressive track record. It saved mankind from the hor- rors of smallpox and helps in preventing diseases and DIALOGUE avoiding all kinds of health hazards. The Netherlands is Community engagement is key to suc- currently going through a period of declining vaccina- cessfully controlling infectious disease tion rates. Vaccination against human papillomavirus outbreaks. That is not only and once (HPV) as well as Herpes Zoster and Rotavirus is met again the lesson learned in the recent with great suspicion and has become controversial, even Ebola virus disease outbreak in DRC; it among some health professionals. also applies to vaccination campaigns in general. The best chances for overcoming low coverage rates are through n the public debate, the confidence in public health a respectful and extensive dialogue authorities is being questioned. There is a great with target groups, in particular when deal of mistrust by a seemingly growing number misconceptions, religious arguments, of people, some of whom allege that the interest of or mistrust of authorities dominate.[4] the population at large seems to prevail over that of A similar approach is needed towards the individual. Some of the so-called 'anti-vaxxers' the debate on voluntary versus man- believeI that measles vaccination may cause autism, point- datory vaccination policies, whereby ing their fingers at the pharmaceutical companies for ignor- sufficient attention should be paid to ing such claims. These perceptions are difficult to combat. what people in concrete societal contexts Drastic solutions like making vaccination obligatory may help think and feel about these themes. A a bit, as well as improving patient-centred counselling, but strained relationship between health they do not fundamentally tackle the root of the problem. authorities, service providers and the general public could be detrimental to The underlying problem is predominantly mistrust. We, the success of vaccination programmes, the Working Party for Family Physicians and International as its success depends on people’s Health (in Dutch: WHIG), recommend that people who have a continued trust and acceptance. medical condition obtain their vaccination from their family practice. Family Physicians (FPs) in the Netherlands are independent professionals who provide continuous integrated Koos van der Velden, PhD, MD, MPH care. They are expected to adhere to guidelines established by Emeritus professor Public health, Radboud their professional organization (NHG, the Dutch College of University Medical Centre, Nijmegen, General Practitioners). The fact that they are seen as inde- the Netherlands. pendent creates trust among their patients, which justifies [email protected] a stronger role for FPs in the provision of vaccinations.

For other public health activities, such as the provision of REFERENCES flu vaccination and cervical cancer screening, FPs receive a

1. https://www.who.int/immunization/newsroom/ decent financial compensation and this has resulted in high new-measles-data-august-2019/en/ 2. https://www.who.int/news-room/fact-sheets/ coverage rates. This shows that general practices are already detail/immunization-coverage an appropriate place of choice for vaccination of specific 3. Visser O. Preventing pertussis in early infancy – Developing of a strategy for implementing target groups, including patients with some kind of health pertussis vaccination of new parents and health care workers. PhD dissertation, Nijmegen, conditions (immune suppression, chronic diseases). In Radboud Institute of Health Sciences, 2018. case patients are hesitant to get vaccinated, FPs commonly 4. Ruijs H. Acceptance of vaccination among orthodox Protestants in the Netherlands. PhD dissertation. use instruments such as counselling and shared decision Nijmegen, Radboud Institute of Health Sciences, 2012. making. The benefits of vaccination need to be weighed against someone's resistance to perceived intrusion or loss of body integrity. Sometimes people are even challenged to give up their religious principles against vaccination.

18 MT BULLETIN OF NVTG 2019 DECEMBER 04 VIEWPOINT

THE INTEREST OF THE CLIENT SHOULD PREVAIL WHEN DECIDING WHO IS BEST PLACED TO PROVIDE VACCINATION SERVICES

Ideally, vaccination should be consid- often received their shot in a sports well established and effective. However, ered a positive choice, weighing the hall, with several of them crying for adult vaccination programmes, there public interest of protecting society and giving the creeps to other girls. is no overarching policy of the Dutch (as in the case of measles) against The logistics were technically safe, government on who should be in the an individual's desire for autonomy. but the circumstances were rather lead or do what. The Ministry of Health Unless public health practitioners off-putting for young girls. Such an (VWS) seems to rely on free market lend an ear to people's concerns and impersonal approach may be neces- forces. There is a divide between the objections and unless parents who sary for a serious disease outbreak municipal health services (GGD) and worry about the possible side-effects but not in this case. Why not opt general practitioners, which is a tragic of vaccination for their young children for the intimacy of the general flaw of our (privatized) health system. are taken seriously, popular sup- practice? Most practices can easily In national health services of countries port for vaccination will dwindle. handle the relatively small num- like the UK, Portugal and Spain, this is bers involved in an inexpensive not so much the case. The divide in the We as FPs postulate that some of the manner, integrating this type of Netherlands not only affects the organ- current policies inhibit optimal ser- vaccination into their daily routine. isation of adult vaccination but also crip- vice provision and are not as effective Because of their personal relation ples other preventive health measures. as one would wish. Some examples: with their clients, FPs are perfectly • As family physicians and mem- capable of managing girls' (and Accepting that general practices run bers of WHIG, we strongly believe boys') and parents' mistrust, if any. by FPs are an appropriate platform in the benefits of travel advice in • For flu vaccination, it seems logical for providing comprehensive health general practice as a low-threshold that multiple target populations are services is in the clients' interest and service for people intending to served by different care provid- may eventually be the most (cost-) travel abroad. Many travelers go on ers. Occupational health services effective strategy to provide vaccina- holiday insufficiently vaccinated offer vaccination to employees, but tion and other preventive measures. We or counselled on other preventive often with disappointing vaccina- hope that the Dutch College of Family measures. This is true in spite tion rates of below 50%. Inviting Health Physicians (NHG) and the of the availability of excellent employees to get vaccination from Association of FPs (LHV), the National scientific advice from the LCR their FPs, with whom they can Institute for Public Health and the (National Coordination Centre for discuss vaccine requirements, Environment (RIVM), the Netherlands Travel Advice). Precisely here a FP could result in a better coverage. Institute for Control of Infectious can make a difference. We think • Future vaccines for pneumococci diseases (NIVB), and patient interest it is a missed opportunity that FPs and herpes zoster could also organisations will endorse our plea. are not facilitated in providing best be administered by FPs. travel advice services. This is also Note: another article, in Dutch, on the same becoming increasingly relevant, as The interest of the client should prevail topic was recently published by Pieter van den Hombergh and Ted van Essen, under the title 'De many (elderly) people with chronic when deciding who is best placed to huisarts heeft de beste papieren om te vaccineren' conditions undertake trips that are provide vaccination services. That seems (Medisch Contact 46, 14 november 2019). not without risk. Certain occupa- common sense. The Dutch health care tional health services (KLM, etc.) system has become a marketplace since and specialist clinics are undisput- 2006, with quite some competition, Pieter van den Hombergh, MD, PhD edly more specialized in providing commercial interests, fragmentation, Family physician, the Netherlands. travel advice than FPs. However, and incoherence. This has caused [email protected] FPs have the advantage of having confusion and undermined the pub- a long-term relation with their cli- lic's confidence, leading to suboptimal Wim Heres, MD ents and being more familiar with vaccination rates. FPs are best placed their family situation, which is all to maintain and update their clients' Family physician, Health Centre Leonardus, Helmond, the Netherlands. the more relevant in case people personal medical files, including their return from abroad with an illness. vaccination status. For children below [email protected] • In the HPV vaccination campaign, five years of age, the national vaccination girls at the sensitive age of 13 years programme (RVP) in the Netherlands is

DECEMBER 04 2019 MT BULLETIN OF NVTG 19 IN MEMORIAM Membership of the Netherlands Society for Tropical Medicine and Wouter W.E. Nolet International Health (NVTG) runs from M.D. Global Health and Tropical Medicine 1 January to 31 December and may commence at any time. Membership will be renewed automatically unless cancelled in writing before 1 December. Membership includes MTb and International Health Alerts. An optional subscription to TM&IH carries an additional cost. Non NVTG members can subscribe to MTb through a student membership of the Society for € 40 per year by sending the registration form via our website www.nvtg.org/lidworden or by sending name and postal address by e-mail to: [email protected] Please submit your contributions and announcements to the editorial office by e-mail: [email protected]

Netherlands Society for Tropical Medicine and International Health

president J.A.E. (Joop) Raams

secretary M.G.P. (Marieke) Lagro

secretariat J.M. (Janneke) Pala-Van Eechoud P.O. Box 43 8130 AA Wijhe | The Netherlands | +31(0)6 156 154 73 | On the 23rd of November 2019, Wouter passed away at the age of 32, due to the [email protected] | www.nvtg.org complications of Lassa fever. COLOPHON We are shocked by the loss of a devoted professional and, for many, a dear friend. MT Bulletin of the Netherlands During his Global Health and Tropical Medicine training, Wouter was a highly Society for Tropical Medicine and involved and much appreciated board member of TROIE and Consult Online. After International Health ISSN 0166-9303 his training, he worked as Programme Coordinator for CapaCare in Sierra Leone. His versatile role included training Masanga’s Community Health Officers and aspiring CHIEF EDITOR Global Health doctors. Leon Bijlmakers

With his many qualities and numerous endeavours, Wouter’s personality and life are EDITORIAL BOARD impossible to capture in a few words. His smile was heart-warming, his choices an Jan Auke Dijkstra, Esther inspiration, and his life exemplary. We will miss him dearly. Jurgens, Olga Knaven, Hanna Kroon, Andrea van Meurs, We wish his family, partner and friends strength; our Carlie Timmers, Ed Zijlstra thoughts are with them. SECRETARIAT Hein Dik Barentsen On behalf of TROIE, Consult Online, MTb and

NVTG LANGUAGE EDITING Eliezer Birnbaum

COVER PHOTO Hanneke de Vries

DESIGN Mevrouw van Mulken

Vaccination: Achievements, Challenges,­ Prospects Editorial

Vaccination: Achievements, Challenges, Prospects Editorial