Relationship between antibody avidity, Fc-mediated functional activity and longevity of malaria vaccine responses in clinical trials

Background Advancing the development of highly efficacious and long-lasting malaria vaccines is hampered by incomplete knowledge of protective immune mechanisms and an absence of established correlates of immunity. Antibody avidity is frequently evaluated as an indicator of a high-quality or protective antibody response to vaccination. However, the importance of avidity in vaccine-induced immunity to malaria remains unclear. Methods/approach We investigated the association between antibody avidity, Fc-mediated functional activities, and antibody longevity in two different Plasmodium falciparum vaccine trials; a phase 1 trial of merozoite surface protein 2 in malaria-naïve adults, and a phase 2b trial of the RTS,S vaccine in African children. Results In both trials, we found that the magnitude of IgG induced by vaccination correlated strongly with antibody avidity indicating the two vaccine immunogenicity outcomes are related. Antibody avidity was not a major determinant of Fc-mediated functional activity, including complement fixation, binding of Fcγ-receptors, or opsonic phagocytosis. In analysis models, IgG magnitude was a stronger determinant of function than IgG avidity. Although avidity positively correlated with antibody functional activities, this was largely due to the confounding effect of the correlation between IgG magnitude and Fc functional activity. Additionally, we found that antibody avidity showed only a weak and antigen-specific association with antibody longevity. Similar findings in the two vaccine trials, which differed by vaccine antigen, adjuvant, and age group, suggests that these observations are likely to be generalisable and not specific to a vaccine type. Conclusion Antibody avidity was not a better predictor of Fc-mediated functional activity than antibody magnitude and avidity was not a strong correlate of antibody longevity. These findings suggest that vaccine approaches that focus on increasing antibody avidity per se may not be sufficient to achieve more efficacious or long-lasting vaccines.