Factors influencing vaccine responses in the first year of life

Abstract

Immunisation is the most cost-effective life-saving medical intervention and is estimated to save at least 2.5 million lives each year. However, there is substantial variation between individuals in the immune response to immunisations. This has consequences for both protective efficacy and duration of protection. My PhD research project focused on evaluating factors that influence antibody responses to routine immunisations given in infancy.

The first section of my thesis focuses on intrinsic, perinatal and external factors that might influence responses to immunisation in infancy. Within this, I investigated the effect of maternal immunisation during pregnancy. Antenatal diphtheria-tetanus-acellular pertussis (dTpa) was associated with significantly reduced infant antibody responses to both specific (diphtheria and pertussis) and heterologous (polio and pneumococcal) vaccines. In contrast, maternal influenza immunisation had minimal effect on infant vaccine responses. I also investigated the effect of early-life factors, namely sex, delivery mode, breastfeeding and antibiotic exposure on antibody responses to routine immunisations given in the first year of life. While there were some differences between males and females in antibody responses to routine immunisations in the first year of life, delivery mode, breastfeeding and antibiotic exposure did not exert a substantial influence.

The second section of my thesis focuses on the ‘non-specific’ or immunomodulatory effects of the Bacillus Calmette-Guerin (BCG) vaccine, one of the most widely used vaccines worldwide, and specifically, how it influences vaccine responses to heterologous (routine) immunisations. It comprises a systematic review of studies that investigated the effect of previous or co-administered BCG on heterologous vaccine responses in infants and adults, and an original study in which I investigated the effect of BCG immunisation at birth on antibody responses to routine infant vaccines. In this study, although not statistically significant, antibody responses in BCG-vaccinated infants were consistently higher against diphtheria, tetanus, pneumococcal, measles and mumps antigens, but lower against Haemophilus influenzae type b compared to BCG-naive infants. These findings add to the evidence that BCG immunisation at birth has broad heterologous effects on the infant immune system.

The third section of my thesis focuses on the correlation between the response to different vaccines, for which there was previously no data available. I found that correlation between antibody responses to similar antigens in the same vaccine (such as different serotypes of a bacterium or virus), as well as responses to antigens conjugated to similar carrier proteins are strong. In contrast, correlation between responses to other vaccines are weak and there is a negative correlation between responses to measles-mumps-rubella vaccine antigens and non-live vaccine antigens. There was also a weak correlation between antibody responses to vaccines of the same type (e.g. polysaccharide or toxoid vaccines). This has important clinical implications as it means the current practice of measuring antibody responses to one or a few vaccine antigens does not offer a reliable surrogate marker of responses to unrelated vaccines.

Recognising factors which might influence vaccine antibody responses, is important for the design of vaccine studies and decisions on vaccine schedules. It also offers ways to optimise vaccine immunogenicity and effectiveness, as well as the possibility to individualise immunisation. The complex interplay between different components of the immune system in vaccine responses is not yet fully understood, and future studies should focus on additional factors, including the innate and cellular immune system.