How advances in immunology provide insight into improving vaccine efficacy

Abstract

Vaccines represent one of the most compelling examples of how biomedical research has improved society by saving lives and dramatically reducing the burden of infectious disease. Despite the importance of vaccinology, we are still in the early stages of understanding how the best vaccines work and how we can achieve better protective efficacy through improved vaccine design. Most successful vaccines have been developed empirically, but recent advances in immunology are beginning to shed new light on the mechanisms of vaccine-mediated protection and development of long-term immunity. Although natural infection will often elicit lifelong immunity, almost all current vaccines require booster vaccination in order to achieve durable protective humoral immune responses, regardless of whether the vaccine is based on infection with replicating live-attenuated vaccine strains of the specific pathogen or whether they are derived from immunization with inactivated, non-replicating vaccines or subunit vaccines. The form of the vaccine antigen (e.g., soluble or particulate/aggregate) appears to play an important role in determining immunogenicity and the interactions between dendritic cells, B cells and T cells in the germinal center are likely to dictate the magnitude and duration of protective immunity. By learning how to optimize these interactions, we may be able to elicit more effective and long-lived immunity with fewer vaccinations.

Keywords: Antibody; Immunological memory; Protection; Vaccination.

Figure 1. Vaccination reduces the incidence of infectious disease

Values represent the number of annual cases of disease that occurred in the United States during the pre-vaccine era (adapted from [2]) compared to the number of cases for each disease reported to the CDC in 2012 [3]. Invasive pneumococcal disease (IPD, Streptococcus pneumoniae) and Haemophilus influenzae type b (Hib) case numbers refer to children <5 years of age. Case numbers for polio include both paralytic and non-paralytic forms of the disease. For varicella, the reported incidence in 2012 was 11,477 cases, but this is likely to be underreported due to challenges in clinical diagnosis of milder vaccine-modified cases [92]. For diseases with an incidence of ≤10 cases in 2012, the number of total cases is indicated in parentheses.

Figure 2. Relationship between long-term immunity and long-term protection

In this illustration, natural infection with a wild-type virus (e.g., measles virus) elicits immunity that peaks shortly after infection, declines for a period of time, and then reaches a plateau phase of long-term maintenance. Following infection with a live, attenuated vaccine (e.g., MMR), the kinetics of the antiviral immune response mirror that observed following natural infection but the level of immunity during the peak and plateau phase may be lower and the plateau may reside at or below the protective threshold and therefore provide only partial protection despite the maintenance of a measurable seropositive immune response. Following booster vaccination, antiviral immunity is increased and if the set point of the new plateau phase resides above the seroprotective threshold, then long-term immunity as well as long-term protection is maintained.

Figure 3. Characteristics of a vaccine antigen determine subsequent levels and duration of immunity

A putative multivalent protein antigen is shown in comparison to a monovalent protein or non-protein antigen. In this example, B cell clones extract antigen from follicular dendritic cells (FDC), followed by processing (protein antigens only) and presentation to T follicular helper (T_FH) cells. Several lines of evidence indicate that multivalent interactions increase B cell receptor (BCR) clustering and improve the ability of B cells to secure antigen from antigen presenting cells [–, –95]. This multivalent interaction also stabilizes the antigen-BCR complex and leads to an increase in peptide-loaded MHC Class II complexes (pMHCII). Increased presentation of pMHCII to cognate CD4⁺ T_FH cells, in addition to other cell-to-cell interactions (e.g., CD40-CD40L, etc.), can lengthen the dwell time between B cells and T cells, improving the survival for a particular B cell clone. Although more studies are needed, the combination of increased BCR clustering and increased antigen presentation to T_FH cells by multivalent proteins may play a role in imprinting an increased plasma cell lifespan and sustained antibody production.