Analysis BMJ Glob Health: first published as 10.1136/bmjgh-2020-003403 on 19 May 2021. Downloaded from Evolving pharmacovigilance requirements with novel vaccines and vaccine components 1 2 3 4 Patrick L F Zuber , Marion Gruber, David C Kaslow, Robert T Chen, Brigitte K Giersing,5 Martin H Friede5 To cite: Zuber PLF, Gruber M, ABSTRACT Summary box Kaslow DC, et al. Evolving This paper explores the pipeline of new and upcoming pharmacovigilance requirements vaccines as it relates to monitoring their safety. Compared ► Novel vaccine technologies include genetic mod- with novel vaccines and vaccine with most currently available vaccines, that are constituted components. BMJ Global Health ifications of micro- organisms, viral vectors, use of live attenuated organisms or inactive products, future 2021;6:e003403. doi:10.1136/ of nucleic acids or novel adjuvants, they also in- vaccines will also be based on new technologies. Several bmjgh-2020-003403 clude increased valences and different routes of products that include such technologies are either administration. already licensed or at an advanced stage of clinical Handling editor Seye Abimbola ► Those new characteristics will modify untoward development. Those include viral vectors, genetically reactions, specific and non- specific, and will also attenuated live organisms, nucleic acid vaccines, novel Received 9 July 2020 require new pharmaco-epidemiological approaches. Revised 4 August 2020 adjuvants, increased number of antigens present in a ► The risk management plans for those products will Accepted 9 August 2020 single vaccine, novel mode of vaccine administration and have to factor those new theoretical concerns and thermostabilisation. The Global Advisory Committee on propose ways of monitoring them during the prod- Vaccine Safety (GACVS) monitors novel vaccines, from the ucts life- cycle. time they become available for large scale use. GACVS ► As several novel vaccines are developed against maintains their safety profile as evidence emerges from diseases prevalent in countries with weak phar- post- licensure surveillance and observational studies. macovigilance systems, vaccine introductions will Vaccines and vaccine formulations produced with novel require establishing active monitoring to rule out se- technologies will have different safety profiles that will rious untoward effects in early adopter populations. require adapting pharmacovigilance approaches. For example, GACVS now considers viral vector templates developed on the model proposed by Brighton http://gh.bmj.com/ Collaboration. The characteristics of those novel products diverse ever vaccine development effort. As at will also have implications for the risk management © Author(s) (or their end July 2020, less than 7 months after iden- employer(s)) 2021. Re- use plans (RMPs). Questions related to the duration of active tification and characterisation of the virus, permitted under CC BY- NC. No monitoring for genetic material, presence of adventitious close to 200 different vaccine products are commercial re- use. See rights agents more easily detected with enhanced biological at different stages of development, including and permissions. Published by screening, or physiological mechanisms of novel adjuvants at least five in phase III trials.1 Candidate on September 25, 2021 by guest. Protected copyright. BMJ. are all considerations that will belong to the preparation of 1 COVID-19 vaccines encompass a broad spec- Access to Medicines and RMPs. In addition to assessing those novel products and Health Products Division, World advising experts, GACVS will also consider how to more trum of products, including classic products Health Organization, Geneva, broadly communicate about risk assessment, so vaccine but also the use of several novel technologies Switzerland such as viral vectors, genetically attenuated 2 users can also benefit from the committee’s advice. Center for Biologics Evaluation live organisms or nucleic acid vaccines. In and Research, Food and Drugs Administration, Silver Spring, addition, future vaccines may also include Massachusetts, USA novel adjuvants, increased number of anti- 3Essential Medicines, PATH, INTRODUCTION gens, novel mode of vaccine administration Seattle, Washington, USA As compared with the 20th century many and thermostabilisation. Those technological 4 Brighton Collaboration, Task recent vaccines, and others currently under developments will also affect untoward reac- Force for Global Health, Decatur, Georgia, USA development, present several novel features tions to vaccine administration, sometimes 5Immunization, Vaccines and that will also impact their safety profile. While towards better tolerance, and will require Biologicals Department, World older vaccines included live attenuated organ- additional monitoring approaches to account Health Organization, Geneva, isms or inactive substances (such as inactivated for the novel characteristics. Switzerland germs, subunits, modified toxins or recombi- For over 20 years, the Global Advisory Correspondence to nant proteins), it is now also possible to apply Committee on Vaccine Safety (GACVS) has Dr Patrick L F Zuber; newer technologies. The recent COVID-19 monitored new vaccines from the time they zuberp@ who. int pandemic has led to the largest and most reach market authorisation. GACVS does Zuber PLF, et al. BMJ Global Health 2021;6:e003403. doi:10.1136/bmjgh-2020-003403 1 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2020-003403 on 19 May 2021. Downloaded from characterise and maintain the safety profile of WHO- landscape analysis of the most advanced and applicable recommended vaccines as evidence emerges from postli- novel platforms. Since these candidates are typically 5–10 censure surveillance and observational studies. GACVS years away from licensure, they present a forward-looking also provides advice of priorities for vaccine safety perspective on innovations to come for WHO to proac- research and normative guidance about preferred meth- tively prepare guidance. odologies. In this review, we describe novel vaccine tech- As the number of WHO-recommended vaccines nologies, with a perspective over the next 10 years. We increases,4 there is a critical need for more effective discuss known and theoretical implications with respect products that are cheaper and easier to deliver. On the to monitoring their safety and also examine how this will production side, healthy markets that provide afford- impact the risk management of novel vaccine products. able essential products in sufficient quantity, with the ability to rapidly manufacture and scale up in response to SITUATION ANALYSIS disease outbreaks, remain an elusive goal. These require- Vaccines and vaccine technologies pipeline ments prioritise technologies that offer one or more of WHO supports vaccines and novel technologies from the following advantages: (1) increased vaccine efficacy early product development through to the publication that enables dose sparing, or a reduction in the number of global policy recommendations.2 WHO’s Product of doses per regimen, such as with genetic attenuation Development for Vaccines Advisory Committee (PDVAC) of live organisms, novel adjuvants and potentially novel facilitates early assessment of pipeline products, typically delivery routes; (2) ability to combine multiple antigens, in clinical phase I or II, for which there is the greatest either from the same pathogen or different pathogens unmet public health need.3 Since its inception in 2014, within the same formulation, possibly with the inclusion PDVAC has reviewed 36 pathogen areas and prioritised of genetic adjuvants to reduce the number of vaccina- 10 urgently required vaccines (figure 1). A key compo- tions, such as through the use of viral vectors and nucleic nent of PDVAC’s remit is horizon scanning of novel acid vaccines, or combinations of individual antigens; candidates, an increasing number of which are based (3) ability to rapidly manufacture low- cost vaccines with on innovative manufacturing, product presentation new antigen sequences in a matter of weeks rather than or delivery technologies. These assessments provide a months, such as with nucleic acid- based platforms and http://gh.bmj.com/ on September 25, 2021 by guest. Protected copyright. Figure 1 Overview of the PDVAC pipeline by novel antigen presentation platform. Regimens involving heterologous prime boost approaches, or candidates incorporating more than one platform are shown as stripped bars. Ebola virus vaccines are overseen by the R&D blueprint, but are included in this PDVAC overview to reflect the pipeline status of novel platforms for this antigen. ETEC, enterotoxigenic Echerichia coli; GAS, group A streptococcus; GBS, group B streptococcus; HSV, herpes simplex virus; PDVAC, product development for vaccines advisory committee; R&D, research and development; RSV, respiratory syncytial virus; TB, tuberculosis. 2 Zuber PLF, et al. BMJ Global Health 2021;6:e003403. doi:10.1136/bmjgh-2020-003403 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2020-003403 on 19 May 2021. Downloaded from (4) improved safety and acceptability of vaccines at the Box 1 Issues of critical importance for viral vector point of delivery, such as through the use of needle-free vaccines (adapted from reference17) and integrated reconstitution technologies. Figure 1 presents an overview of the vaccine candidates ► Potential recombination with wild- type pathogenic strains. for the