Analysis BMJ Glob Health: first published as 10.1136/bmjgh-2020-003814 on 19 May 2021. Downloaded from Novel vaccine safety issues and areas that would benefit from further research 1 2 3 4 Daniel A Salmon , Paul Henri Lambert, Hanna M Nohynek, Julianne Gee, Umesh D Parashar,5 Jacqueline E Tate,5 Annelies Wilder- Smith,6 7 8 9 Kenneth Y Hartigan- Go, Peter G Smith, Patrick Louis F Zuber To cite: Salmon DA, ABSTRACT Summary box Lambert PH, Nohynek HM, Vaccine licensure requires a very high safety standard et al. Novel vaccine safety and vaccines routinely used are very safe. Vaccine safety ► Adverse events following immunization that are rare, issues and areas that monitoring prelicensure and postlicensure enables would benefit from further happen in subpopulations, and have delayed onset continual assessment to ensure the benefits outweigh the research. BMJ Global Health are monitored post- licensure. risks and, when safety problems arise, they are quickly 2021;6:e003814. doi:10.1136/ ► Vaccine adverse reactions can be related to identified, characterised and further problems prevented bmjgh-2020-003814 genomics. when possible. We review five vaccine safety case studies: ► There are opportunities for additional research to (1) dengue vaccine and enhanced dengue disease, (2) Handling editor Seye Abimbola fully define the safety profile of vaccines. pandemic influenza vaccine and narcolepsy, (3) rotavirus ► Unanswered safety questions and real safety prob- vaccine and intussusception, (4) human papillomavirus Received 28 August 2020 lems can undermine public confidence in vaccines. Revised 1 December 2020 vaccine and postural orthostatic tachycardia syndrome and ► Transparent and timely communication about ad- Accepted 6 January 2021 complex regional pain syndrome, and (5) RTS,S/adjuvant verse events following immunization is crucial to system 01 malaria vaccine and meningitis, cerebral maintaining public trust. malaria, female mortality and rebound severe malaria. These case studies were selected because they are recent and varied in the vaccine safety challenges they elucidate. Bringing these case studies together, we develop lessons 2. Pandemic influenza vaccine and narcolep- learned that can be useful for addressing some of the sy. potential safety issues that will inevitably arise with new 3. Rotavirus vaccine and intussusception. vaccines. 4. Human papillomavirus (HPV) vaccine and postural orthostatic tachycardia syndrome http://gh.bmj.com/ (POTS) and complex regional pain syn- drome (CRPS). INTRODUCTION 5. RTS,S/AS01 malaria vaccine and meningi- tis, cerebral malaria, female mortality and Vaccines are held to a very high safety rebound severe malaria. standard as they are given to healthy individ- For each of these case studies, we review the on September 30, 2021 by guest. Protected copyright. uals to prevent rather than to treat disease, safety issues that have been identified, poten- often administered to a large proportion of tial biological mechanisms, epidemiological the population, and their use is supported by data, and finally, conclusions about causality governments and health authorities. Vaccines and areas for future research. These case routinely used are very safe and, while adverse studies were selected because they are recent reactions do occur, serious adverse reactions and varied in the vaccine safety challenges are very rare. Vaccine safety is monitored they elucidate. Bringing these case studies throughout the product life cycle—from together, we develop lessons learnt that can research and development through postlicen- be useful for addressing some of the potential © Author(s) (or their sure surveillance. This ensures that routinely safety issues that will inevitably arise with new employer(s)) 2021. Re- use used vaccines are very safe, the benefits permitted under CC BY-NC. No vaccines. commercial re- use. See rights outweigh the risks in the populations for and permissions. Published by which they are indicated and safety problems BMJ. if they arise are quickly identified, character- DENGUE VACCINE AND ENHANCED DENGUE For numbered affiliations see ised and further problems prevented when DISEASE end of article. possible. Dengue poses a significant public health Correspondence to In this paper, we review five vaccine safety problem in the tropics and subtropics with 1 Dr Daniel A Salmon; case studies (box 1): as many as 390 million infections annually. dsalmon1@ jhu. edu 1. Dengue vaccine and enhanced disease. After decades of research, the world’s first Salmon DA, et al. BMJ Global Health 2021;6:e003814. doi:10.1136/bmjgh-2020-003814 1 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2020-003814 on 19 May 2021. Downloaded from phase 3 clinical trial programme indicated that protec- Box 1 Summary of case study elements and key lessons tive efficacy varied according to serostatus prior to vacci- 4 Dengue vaccine and enhanced dengue disease nation and serotype. Vaccine- induced immunogenicity Dengvaxia was protective for seropositive vaccinees; seronegative was not predictive of protective clinical efficacy, and no vaccinees had an increased risk of hospitalisation and severe dengue. immune correlates (for protection or enhancing disease) Recommendations for vaccination only for dengue- seropositive were established.4 people. In the phase 3 trial, excess hospitalisations for dengue Key lessons: Need more understanding of impact of natural disease were observed among vaccine recipients 2–5 years of age. on vaccines. Precise risk estimates according to dengue serostatus Pandemic influenza vaccine and narcolepsy prior to vaccination could not be ascertained because Small but significant increase in narcolepsy following one adjuvanted of the limited numbers of samples collected at baseline. pandemic influenza vaccine. Pandemrix in Sweden, Finland, and UK A post hoc analysis of safety and efficacy used a novel (various rates, highest 1:16 000); the Sleep Apnoea Monitoring with Non-Invasive Applications study (1:18 400). dengue anti- non- structural protein 1 (NS1) IgG ELISA Key lessons: Postlicensure studies in large populations with different on samples from month 13 to retrospectively infer base- genetic backgrounds is important. Timing of vaccination during an line serostatus. These analyses showed that in seropositive outbreak may be important. trial participants aged 9–16 years, in the 66 months after Rotavirus vaccine and intussusception administration of the first vaccine dose, the vaccine was RotaShield was the first rotavirus vaccine on the market with protective. HRs, comparing vaccinated to placebo recip- intussusception rates of 1:10 000 (postlicensure). Concerns of higher ients, for hospitalised virologically confirmed dengue risk if given before 3 months led to age restriction; risk–benefit (VCD) and severe VCD, were 0.21 (95% CI 0.14 to 0.31) analysis led to discarding restriction. RotaShield was eventually pulled and 0.16 (95% CI 0.07 to 0.37), respectively. However, from market. in seronegative participants aged 9–16 years, vaccinees RotaTeq and Rotarix, next on the market, underwent large clinical had an increased risk of hospitalised and severe dengue, trials with intussusception rates 1-5:100 000 in high- income and with corresponding HRs of 1.41 (95% CI 0.74 to 2.68) middle- income countries; Rotarix showed no elevated risks in low- 5 income and middle- income country (no data from RotaTeq). and 2.44 (95% CI 0.47 to 12.56), respectively. A plau- Key lessons: Postlicensure studies in large populations are essential. sible hypothesis for these findings is that the vaccine acts Human papillomavirus vaccine and postural orthostatic as a ‘silent infection’, so that the first natural infection tachycardia syndrome and complex regional pain syndrome in seronegative recipients is then ‘secondary- like’, with Concerns over complex regional pain syndrome and postural an associated increased risk of severe disease, whereas orthostatic tachycardia syndrome following the human papillomavirus in seropositive recipients the first natural infection after vaccines on the market, Cervarix, Gardasil and Gardasil-9, led to lower vaccination is ‘tertiary- like’, which is not associated with a coverage, confidence and some loss of country recommendations. higher risk of severe disease.6 In December 2017, Global Vaccine adverse event reporting system, European Medical Agency, Advisory Committee on Vaccine Safety (GACVS) recom- Global Advisory Committee on Vaccine Safety and AAS and large-scale mended that Dengvaxia should only be administered to http://gh.bmj.com/ studies found no signals or patterns. individuals who had been previously infected with wild Key lessons: Postlicensure studies in large populations are essential 7 and effective communication about safety is vital dengue virus. Based on WHO’s Strategic Advisory Group RTS,S/adjuvant system 1 malaria vaccine and serious adverse of Experts (SAGE) recommendations, WHO’s posi- events tion published in 2018 is that for countries considering ► Exploratory analyses in phase 3 trial showed. Dengvaxia vaccination as part of their dengue control ► Meningitis: increase risk of meningitis in two trial sites in one age programme, a prevaccination screening strategy, in on September 30, 2021 by guest. Protected copyright. group; regarded as potential signal. which only dengue- seropositive persons are vaccinated, ► Cerebral malaria: increased in vaccinees versus controls. is recommended. 8 ► Mortality: increased mortality in vaccinated