How Children's Immune Systems 'Learn' to Recognize Strep A—and What It Means for a Future Vaccine

Streptococcus pyogenes – the aforementioned Group A streptococcus – seems like a harmless cold companion, but it is responsible for tonsillitis, impetigo (pyoderma), scarlet fever and, in severe cases, rheumatic heart disease. It is associated with about half a million deaths each year, with the main burden falling on low- and middle-income countries. A vaccine could radically change the picture, but there is a fundamental question on the way: what natural defenses are formed in humans at all, and what are the bacteria “targeting”?

A team of researchers in Gambia answered this question in the most "live" way possible: they observed families for a year, regularly taking throat and skin swabs, as well as blood tests - from newborns to the elderly. The result is a rare "film" in detail about how humoral immunity (antibodies) is built up in people as they come into contact with the bacteria, and which antibodies are associated with real protection against new episodes of infection. The study was published in the journal Nature Medicine.

What exactly was studied?

The scientists looked at antibodies to two classes of bacterial targets:

1. Conserved antigens are regions common to many strains:

• SLO (streptolysin O): a toxin that destroys blood cells.
• SpyCEP: An enzyme that “cuts” signaling molecules (such as IL-8), preventing immune cells from arriving at the site of infection.
• SpyAD: A multi-tasking protein important for bacterial attachment and division.
• GAC: group carbohydrate on the surface of streptococcus.

Plus, DNaseB was measured, often as a “beacon” of recent contact with bacteria.

2. The M protein is the most "immunogenic" on the surface of S. pyogenes. Its tip varies greatly from strain to strain (there are hundreds of them, hence the "emm types"). Antibodies to it are usually type-specific: they hit "their" type very well, but are worse at others.

At the same time, functional tests were performed: does serum with a high level of these antibodies really do something - block the toxin, interfere with the enzyme, help immune cells “eat” bacteria.

Design: from maternity hospital to yard

• Mother-infant cohort (94 pairs): maternal and cord blood at birth, then several points in the first year of the child's life.
• Households (SpyCATS): 442 people in 44 families, monthly visits plus unscheduled visits for symptoms. Over 13 months: 108 episodes of illness (mostly pyoderma) and 90 episodes of carriage (bacteria present, no symptoms).

This is important: in the Gambia, pyoderma and carriage are not uncommon, children often come into contact with different strains quite early.

The most interesting - point by point

1) Maternal antibodies are present... and quickly disappear

Through the placenta, infants receive fairly decent levels of IgG to SLO/SpyAD/SpyCEP (worse — to the carbohydrate GAC). But in the first months, these antibodies subside. By 9–11 months, approximately every fourth child (23%) experiences a serological “jump” — a sure sign of their first contact with the bacteria and the beginning of the formation of their own protection.

2) Antibody surges are strongest in children <2 years old

And this is after any events: tonsillitis, pyoderma and even asymptomatic carriage - both in the pharynx and on the skin. It is logical: the lower the "base" bar, the higher the "wave" after meeting the antigen.

3) Key finding: High levels of antibodies to SLO, SpyAD and SpyCEP are associated with a lower risk of new events

The authors carefully showed that if the IgG level to these three conservative antigens is above a certain threshold, the chance that a culture-confirmed episode (disease or carriage) will appear in the coming weeks is lower. And the effect persisted even if we took into account age, gender, family size and… levels of antibodies to the M-protein.

Translation into human: antibodies to common targets for strains are not just a pretty graph. They are really connected to practical protection.

Moreover, if several of these antibodies were high at once, the protection looked stronger - like layers of armor.

4) Do these antibodies actually “work”?

Yes. Where the "binding" IgG were higher:

• the serum was better at suppressing hemolysis from the SLO toxin,
• more strongly interfered with the SpyCEP enzyme's ability to "cut" IL-8,
• significantly increased opsoniphagocytosis (immune cells more readily “packaged” targets) - both with particles and with whole emm1 bacteria.

5) What about antibodies to M-protein?

They also grow after events - but, as expected, more strongly to "their" type (homologous), weaker to "relatives" within the cluster, and almost not at all to "foreigners." Higher "cluster-relevant" antibodies to the M protein were also associated with a decrease in risk. But - and this is important - even taking into account anti-M, the connection of protection with antibodies to SLO/SpyAD/SpyCEP remained independent.

Why This Is a Big Step for the Vaccine

There are two main strategies:

• Multivalent vaccines on top of the M protein: give a "cocktail" of the most common emm types and hope for cross-protection within the "clusters". The problem is that in countries like Gambia, the strains are extremely diverse, and it is difficult to get "into the top".
• Vaccines for conservative antigens (SLO, SpyCEP, SpyAD, GAC, etc.): theoretically a “broad umbrella” against many strains.

The novelty of this study is that it has been shown in real life: high levels of antibodies to SLO/SpyAD/SpyCEP are about protection. Not only in mice and in a test tube. This is a serious argument in favor of including these targets in candidate vaccines, especially for regions with a motley "zoo" of emm types.

When to vaccinate?

The data suggests two scenarios:

• Early: by 11 months, a significant proportion of children have already become familiar with streptococcus, and by 2 years, there is a vigorous "tuning" of the immune system. Early vaccination could intercept primary and repeated episodes that may "prime" dangerous autoimmune consequences (rheumatism).
• And later it is useful: even teenagers and adults do not all have antibodies to conservative antigens “at the level”, so the booster effect of the vaccine is also not superfluous.

The precise age-specific strategy should be determined by clinical trials and disease burden modelling.

What about pyoderma versus tonsillitis?

The researchers saw the strongest protective signal for carriage in the pharynx. For skin episodes, the contribution of the environment (microtraumas of the skin, hygiene, heat/humidity) can "shout down" the role of antibodies. This is important for trial planning: the endpoints are pharyngitis and pyoderma, but one should not expect the same effect.

Limitations so as not to overestimate

• The culture is less sensitive than PCR: some episodes could have been missed.
• A monthly interval of visits does not catch short bursts of carriage.
• Tests for some M-peptides had limited specificity (the authors performed sensitive assays to account for this).
• There was not enough power to separate the “protection thresholds” for the disease and the carrier state.

However, the findings are robust because:

• the analysis was carried out at many points throughout the year,
• functional tests were used (not only "Indiax antibodies"),
• Age, gender, family size and anti-M levels were taken into account.

What's next?

• Trials of SLO/SpyAD/SpyCEP (and possibly GAC) vaccines in high-burden countries – including in children under 2 years of age.
• Standardisation of serological tests so that 'protection thresholds' can be compared between centres.
• Longer cohort observations to understand the duration of protection and its association with specific clinical endpoints (angina, pyoderma, rheumatism).

The main thing in one paragraph

In highly endemic environments, children are exposed to streptococcal A very early and frequently. The strongest antibody responses are in infants under 2 years of age. High levels of antibodies to SLO, SpyAD, and SpyCEP in humans are associated with a lower risk of new episodes of infection, and these antibodies are functionally “working.” This is a strong argument for vaccine strategies targeting conserved antigens (in addition to M protein) and for considering early ages of vaccination.