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.

Keywords: Fc function; Fc receptor; IgG glycosylation; allotype; antibody; computational modelling; polymorphism; vaccine design.

Figure 1

Antibodies comprise two fragment antigen binding (Fab) regions and one fragment crystallisable (Fc) region connected by a ladder-like hinge region. The Fab is responsible for antigen recognition and mediates pathogen and toxin neutralisation. The Fc engages effector cells and molecules of the innate immune system to mediate Fc effector functions. Neutralisation and Fc effector functions each have various advantages and disadvantages but largely counterbalance the shortcomings of the other. *Durable neutralisation capacity and prophylactic Fc functions observed for antibodies against some bacterial pathogens.

Figure 2

Antibody-dependent Fc effector functions referenced throughout this review. Fc effector functions are initiated upon simultaneous antibody engagement with a pathogen antigen and an innate effector molecule (complement component 1q (C1q) or mannose-binding lectin (MBL)) or Fc receptor (FcR) expressed by innate immune cells. Activation of C1q or MBL following antigen binding triggers the complement cascade leading to pathogen or infected cell death via antibody-dependent complement deposition. FcR cross-linking via antibody-antigen complexes triggers downstream signalling cascades within innate effector cells leading to pathogen killing and clearance via a range of antibody-dependent cellular effector functions, listed in the figure. Finally, these effector functions trigger downstream cytokine release which may enable further recruitment of effector cells.

Figure 3

The immunoglobulin heavy (IGH) locus encodes the constant regions of immunoglobulin (Ig) M, IgD, IgG, IgA, and IgE. The constant heavy genes are located downstream of the joining region heavy (JH) genes. One pseudogene (ψCϵ) is also located within the IGH locus. IgG and IgA comprise four and two subclasses, respectively. Additional antibody variation is introduced by the single nucleotide polymorphisms which, alone or in combination, define a range of IgG1, IgG2, IgG3, IgG4, and IgA2 allotypes. Allotypes are listed according to the WHO/IUIS nomenclature in bold, followed by the previous alphabetical notation italicised in brackets. ‘Gm’ or ‘Am’ designates a marker of IgG1-4 or IgA, respectively, followed by a number corresponding to the named allele. ^The prefix ‘n’ or suffix '..' indicates the absence of the allotypic marker at the named allele; these are referred to as isoallotypes and contain an amino acid distinct to the subclass but common across the isotype. (Note that ‘nG1m1’ may be written as ‘G1m-1’ to indicate the absence of the G1m1 allotype). Each named allele is located at a distinct amino position except G1m17 and G1m3 which represent allotypes at the same position.

Figure 4

IgG is post-translationally glycosylated. Biantennary N-linked glycan chains are added at asparagine 297 within the Fc portion of the constant heavy (C_H) regions of IgG. Two N-acetylglucosamine (GlcNAc) subunits and three mannose subunits form two branching structures upon which additional GlcNAc, followed by galactose and then sialic acid are added. Fucose can be linked to the N₂₉₇ proximal GlcNAc and is present on the majority of human IgG.

Figure 5

IgG Fc glycan structures have variable inflammatory properties. IgG Fc glycans differentially modulate Fc effector functions and, therefore, inflammation, depending on the interactions of the sugars with various Fc receptors and complement proteins. In general, lack of fucose is highly inflammatory while the presence of galactose and sialic acid is anti-inflammatory. Total IgG Fc glycosylation varies considerably with age, sex, and health status. In general, there is a greater abundance of pro-inflammatory Fc glycans in elderly individuals with chronic comorbidities, such as obesity, and this is particularly elevated in post-menopausal women. On the other end of the spectrum, pregnancy is associated with increased abundance of anti-inflammatory Fc glycans. Among healthy young adults, women typically have a slightly more anti-inflammatory Fc glycan profile.

Figure 6

Geographic distribution of dominant IgG haplotypes. IgG allotypes are inherited as haplotype blocks and thus show geographic clustering within ethnicities. Data compiled from (449).

Figure 7

Considerations for the design of precision vaccines for vulnerable populations. Age, sex, immunogenetic, and baseline health variations within a vaccinated population can impact vaccine effectiveness. This population variation influences immune features known to modulate vaccine immunogenicity. However, precision vaccines designed to selectively boost the immune features that are impaired or dysregulated in vulnerable populations may enhance vaccine-induced protection. Design of such population-based precision vaccine strategies will require elucidation of the best combinations of antigen and adjuvant, vaccine formulation, and delivery mode in order to elicit an optimised polyfunctional antibody response and promote increased protection response.