Correlates of immunity to Group A Streptococcus: a pathway to vaccine development

Abstract

Understanding immunity in humans to Group A Streptococcus (Strep A) is critical for the development of successful vaccines to prevent the morbidity and mortality attributed to Strep A infections. Despite decades of effort, no licensed vaccine against Strep A exists and immune correlates of protection are lacking; a major impediment to vaccine development. In the absence of a vaccine, we can take cues from the development of natural immunity to Strep A in humans to identify immune correlates of protection. The age stratification of incidence of acute Strep A infections, peaking in young children and waning in early adulthood, coincides with the development of specific immune responses. Therefore, understanding the immune mechanisms involved in natural protection from acute Strep A infection is critical to identifying immune correlates to inform vaccine development. This perspective summarises the findings from natural infection studies, existing assays of immunity to Strep A, and highlights the gaps in knowledge to guide the development of Strep A vaccines and associated correlates of protection.

Disruption of IL-17 signaling in the respiratory mucosa results in invasive streptococcal infection

“…Interestingly, protective immunity in the respiratory mucosa did not rely heavily on germinal center activation or circulating antibodies as mice with low M-specific IgG antibody were still protected after a single infection. Low levels of circulating M-typespecific antibodies during active infection are unsurprising, potentially stemming from IgG cleavage by specific proteases or due to binding to S. pyogenes followed by subsequent removal (Frost, Excler et al, 2023). Interestingly, we observed an increase in IgG and IgA secreting cells in the bone marrow following sequential IN infections, aligning with our previous findings that S. pyogenes skin infections gradually increased the number of M-type-specific antibody-secreting cells in the bone marrow which led to increased protection (Pandey et al, 2016a).…”

The Streptococcus pyogenes vaccine landscape

“…SAVAC has highlighted the favourable cost effectiveness and return on investment of a S. pyogenes vaccine, as well as a series of key knowledge gaps. These gaps include: the scarcity of epidemiologic and economic data from low-and middle-income countries; incomplete understanding of measures of protection against S. pyogenes infection; the identification of immune correlates of protection against S. pyogenes infection, and the development of relevant new functional assays, the current absence of which represents a major impediment to vaccine development the identification of immune correlates of protection against S. pyogenes infection, and the development of relevant new functional assays still lacking and representing a major impediment to vaccine development 54 ; the requirement for standardisation of safety surveillance; and the need for concerted advocacy efforts to raise the profile of the burden of S. pyogenes disease and how a vaccine could address this burden. The next phase of SAVAC's work will be focused on filling these gaps by coordinating research to generate better burden of disease estimates, drawing together relevant stakeholders to establish guardrails for safety surveillance, boosting efforts around advocacy, and a range of other engagement activities.…”

Streptococcus pyogenespharyngitis elicits diverse antibody responses to key vaccine antigens influenced by the imprint of past infections

“…Critically, there is no established human immune correlate of protection to predict efficacy of S. pyogenes vaccines 8 . The epidemiology of S. pyogenes infections strongly suggests that partial immune protection accumulates with repeated exposure through childhood [8][9][10] .…”

“…However, unlike vaccine-preventable bacterial diseases caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, there are no primary or acquired immunodeficiency syndromes classically associated with susceptibility to S. pyogenes infection from which the basis for naturally acquired protection may be inferred. The contribution of M protein serotype-or emm genotype-specific humoral immunity, initially established by streptococcal research pioneer Rebecca Lancefield 11 , remains uncertain 8 , with mixed findings from longitudinal cohort studies [12][13][14][15] , historical human challenge trials [16][17][18][19] , animal models 20 , and in vitro assays 21 .…”

“…Critically, there is no established human immune correlate of protection to predict efficacy of S. pyogenes vaccines 8 . The epidemiology of S. pyogenes infections strongly suggests that partial immune protection accumulates with repeated exposure through childhood 8–10 . However, unlike vaccine-preventable bacterial diseases caused by Streptococcus pneumoniae , Haemophilus influenzae and Neisseria meningitidis , there are no primary or acquired immunodeficiency syndromes classically associated with susceptibility to S. pyogenes infection from which the basis for naturally acquired protection may be inferred.…”