Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations

Abstract

Vaccine efficacy determined within the controlled environment of a clinical trial is usually substantially greater than real-world vaccine effectiveness. Typically, this results from reduced protection of immunologically vulnerable populations, such as children, elderly individuals and people with chronic comorbidities. Consequently, these high-risk groups are frequently recommended tailored immunisation schedules to boost responses. In addition, diverse groups of healthy adults may also be variably protected by the same vaccine regimen. Current population-based vaccination strategies that consider basic clinical parameters offer a glimpse into what may be achievable if more nuanced aspects of the immune response are considered in vaccine design. To date, vaccine development has been largely empirical. However, next-generation approaches require more rational strategies. We foresee a generation of precision vaccines that consider the mechanistic basis of vaccine response variations associated with both immunogenetic and baseline health differences. Recent efforts have highlighted the importance of balanced and diverse extra-neutralising antibody functions for vaccine-induced protection. However, in immunologically vulnerable populations, significant modulation of polyfunctional antibody responses that mediate both neutralisation and effector functions has been observed. Here, we review the current understanding of key genetic and inflammatory modulators of antibody polyfunctionality that affect vaccination outcomes and consider how this knowledge may be harnessed to tailor vaccine design for improved public health.

Antibody glycosylation correlates with disease progression in SIV‐Mycobacterium tuberculosis coinfected cynomolgus macaques

“…Changes in bulk IgG glycosylation profiles have also been observed in other acute and chronic infectious diseases and have been well described to reflect the increased inflammatory state and severity of individuals with a range of autoimmune diseases. 5,[26][27][28] Reduced fucosylation has been described previously in humans following HIV infection. 11 Likewise, changes in bulk IgG glycan profiles towards agalactosylation are observed early during acute (first 5 months) HIV infection and in ATB disease in human cohorts.…”

“…Interestingly, analysis of glycan profiles as a whole was more correlative than examining singular glycan structures as multivariate analysis can capture global changes in glycosylation, likely given there are several potential glycan structures that can be associated with inflammatory or anti-inflammatory states. 5,26 In addition to changes in bulk IgG glycan structures, reduced levels of Mtb-specific antibodies and FccR-binding were apparent 8 weeks following Mtb infection in SIV-coinfected animals. Human studies have provided evidence for antibody titres against specific Mtb antigens.…”

Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

“…This sequence diversity has been most comprehensively characterised for IgG and IgA, with IgG3, followed by IgG1, demonstrating the most extensive variation. 3 …”

“…IgG1 is the most abundant immunoglobulin in humans, constituting approximately 65% of IgG. 7 , 8 IgG1 is important for protection against infectious agents 3 , 7 , 9 , 10 and cancer, 11 , 12 while also implicated in autoimmune diseases. 13 , 14 Four IgG1 allotypic markers (G1m) have been defined: G1m1, G1m2, G1m3 and G1m17 (Figure 1b ).…”

“…For example, the G1m‐1,3 haplotype is dominant in individuals of European descent, while the G1m1,17 haplotype is more prevalent, reaching frequencies over 80%, within African and Asian populations as well as American and Australian First Nations peoples. 3 , 15 , 16 …”