The non-specific and sex-differential effects of vaccines

The textbook view of vaccination is that it functions to induce immune memory of the specific pathogen components of the vaccine, leading to a quantitatively and qualitatively better response if the host is exposed to infection with the same pathogen. However, evidence accumulated over the past few decades increasingly suggests that vaccines can also have non-specific effects on unrelated infections and diseases, with important implications for childhood mortality particularly in low-income settings. Furthermore, many of these non-specific effects, as well as the pathogen-specific effects, of vaccines show differences between the sexes. Here, members of the Optimmunize consortium discuss the evidence for and potential mechanisms of non-specific and sex-differential effects of vaccines, as well as their potential policy implications. Given that the non-specific effects of some vaccines are now being tested for their ability to protect against COVID-19, the authors also comment on the broader implications of these trials. The contributors Peter Aaby was trained as an anthropologist but has built a large health surveillance system in Guinea-Bissau since 1978, focusing on the high levels of child mortality there. Crowding and intensive exposure to measles were key determinants of child mortality. This led to vaccine research and the discovery of the non-specific effects of measles vaccine. Christine Stabell Benn is a professor in global health at the University of Southern Denmark. She conducts epidemiological and immunological studies of vaccines and vitamin A, with a focus on their real-life effects on overall health in Africa and Denmark. She formulated the hypothesis that these health interventions with immunomodulatory effects interact, often in a sex-differential manner. Katie L. Flanagan is Director of Infectious Diseases for north/north-west Tasmania, an adjunct professor at the University of Tasmania and RMIT University and an adjunct associate professor at Monash University. She is Honorary Secretary of the Australasian Society for Infectious Diseases (ASID), Chair of the ASID Vaccination Special Interest Group and a member of the Australian Technical Advisory Group on Immunisation. Her current research focuses on using systems vaccinology to study the sex-differential and non-targeted effects of vaccines. Sabra L. Klein is a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. She is an expert on sex and gender differences in immune responses and susceptibility to infection. She is the immediate past president of the Organization for the Study of Sex Differences, a principal investigator of the Johns Hopkins Specialized Center for Research Excellence in sex and age differences in immunity to influenza and a co-director of the Johns Hopkins Center for Women's Health, Sex, and Gender Research. Tobias R. Kollmann is a paediatric infectious disease clinician and systems vaccinologist at Telethon Kids Institute and Perth Children's Hospital in Perth, Australia. His expertise centres on newborn infectious diseases, immune ontogeny and early-life vaccine responses, using cutting-edge technology and analytics to extract the most information out of the typically small biological samples obtainable in early life. David J. Lynn is Director of the Computational and Systems Biology Program and an EMBL Australia group leader at the South Australian Health and Medical Research Institute. He is also a professor at the Flinders University College of Medicine and Public Health. He leads a research programme in systems immunology, investigating how pathogenic and commensal microorganisms modulate the immune system in different contexts, including vaccination. Frank Shann worked as a paediatrician in Papua New Guinea and then for 20 years was Director of Intensive Care at the Royal Children's Hospital in Melbourne, Australia. He is a professorial fellow in the Department of Paediatrics, University of Melbourne, engaged in research on the non-specific effects of vaccines. In this Viewpoint article, members of the Optimmunize consortium discuss the evidence for non-specific and sex-differential effects of vaccines and how this information might inform vaccine design and policy, including in relation to the COVID-19 pandemic.