Serogroup C meningococcal conjugate vaccines: immunogenicity, immune persistence and induction of immunological memory

Abstract

Background and Aims In the United Kingdom (UK), serogroup C meningococcal (MenC) conjugate vaccines were introduced into the routine infant immunisation schedule in 1999. Subsequently, there was a dramatic decline in the rates of MenC disease in all age groups, including un-immunised infants and adults with the establishment of herd immunity. However, as with Haemophilus influenzae type b (Hib) conjugate vaccines, there is a rapid waning of vaccine induced antibody after primary infant immunisations with MenC conjugate vaccines, associated with a decline in vaccine effectiveness beyond one year after early infant immunisation. The current schedule of MenC immunisations in the UK includes two primary doses at 3 and 4 months of age, and a booster dose of Hib-MenC-TT (tetanus toxoid) conjugate vaccine at 12 months of age. However, beyond infancy, the highest rates of meningococcal disease are seen in adolescents and young adults, who are also the drivers for transmission with the highest rates of nasopharyngeal colonisation. Thus, a series of clinical vaccine trials were carried out to evaluate the effects of different carrier proteins used, and different priming schedules of MenC conjugate vaccines on their immunogenicity and their ability to induce immune memory in infants, and the persistence of immune response following vaccination, throughout childhood. Methods The clinical trials reported here were undertaken in research sites in the UK, Canada, Poland and Malta. Immunogenicity and immune persistence was evaluated by measuring MenC serum bactericidal antibody (SBA) titres in infants and children, with serial measurements assessed over time through childhood and early adolescence. Immune memory was evaluated by measuring memory B cell responses using Enzyme-linked immunospot (ELISpot). Healthy children were invited to participate in these trials through mail-outs based on birth cohorts, as well as re-invitation of children previously enrolled in vaccine trials (for follow-on studies). Results There is a greater bactericidal antibody response following a toddler booster dose of Hib-MenC-TT in children previously primed with Hib-MenC-TT given either at the same time, or as part of a combination vaccine with concomitant diphtheria, tetanus, acellular pertussis and polio (DTPa-IPV) vaccines, than in children previously primed with MenC-CRM197 (diphtheria cross reactive material) conjugate vaccine. This is despite higher antibody levels demonstrated one month after the primary vaccines in children who had received monovalent MenC-CRM197 vaccines. These differences persist to at least 5 years of age. Serogroup-specific bactericidal antibody also wane until 5 years of age following infant immunisation with a combination serogroup A, C, W135 and Y meningococcal (MenACWY-CRM197) conjugate vaccine, most markedly against serogroup A, and least against serogroup W135. By 11 to 13 years of age the percentage of children with MenC SBA titres above the threshold for protection have declined to 15% in a cohort of children who had received a single dose of MenC conjugate vaccine as pre-schoolers, with the odds of protection falling by 23% each year following immunisation. Bactericidal antibody levels also decreased by around 8% each year following immunisation. No differences were seen in the number of memory B cells generated following either 1 or 2 primary doses of MenC-CRM197. No evidence was seen for a relationship in the number of priming doses of an antigen, and the number of antigen-specific memory B cells generated following a booster (for MenC, diphtheria and tetanus). One month following a Hib-MenC-TT booster, children primed with 1 dose MenC-TT had more MenC memory B cells than children primed with either 1 or 2 doses of MenCCRM197. Conclusions Vaccines used for infant immunisation against MenC differ in their ability to prime responses to a booster dose of Hib-MenC-TT, possibly mediated through their ability to stimulate the generation of memory B cells. The greatest antibody and memory B cell responses to MenC conjugate vaccines are associated with the use of TT carrier protein for both priming and boosting. Adequate levels of circulating bactericidal antibody cannot be maintained beyond early childhood following infant and toddler immunisation schedules, and an adolescent booster dose of MenC vaccine is necessary to maintain immunity through this critical age.