A protein-based COVID booster matched mRNA-primed teens' immune response in a small trial

Most adolescents who have had a COVID-19 booster received an mRNA vaccine. But not every country or family favours mRNA, and some teenagers cannot or will not take one, which leaves a gap for alternatives built on older, protein-based technology. A trial published on 23 October in Pediatrics tested one such option — a protein vaccine called PHH-1V — as a booster in adolescents who had been primed with Pfizer's BNT162b2 [s1].

What was tested

PHH-1V is a protein-based, non-mRNA, bivalent, adjuvanted COVID-19 vaccine that had already shown strong immune responses and acceptable safety as a booster in adults [s1]. The question here was whether it would do the same in younger people.

The study, called HIPRA-HH-3, was a phase 2b, open-label, multicentre, non-inferiority trial [s1][s2]. It enrolled 240 healthy adolescents aged 12 to under 18, all of whom had completed a primary course of the Pfizer vaccine [s1][s2]. A non-inferiority design does not try to show the new booster is better; it asks whether the immune response it produces is not meaningfully worse than a comparison group — in this case young adults, aged 18 to 25, from an earlier trial who had also received a PHH-1V booster [s1].

Immune responses were measured in a subset: 90 adolescents compared against 81 young adults [s1]. Researchers looked at neutralising antibodies — the kind that block the virus from entering cells — against several SARS-CoV-2 variants, along with total binding antibodies and T-cell responses, the arm of immunity that helps clear infected cells [s1]. Antibody durability and side effects were tracked out to day 336, nearly a year [s1].

What it found

The adolescents responded at least as well as the young adults, and on several measures better. Neutralising antibody titres against the Omicron BA.1 variant — the trial's primary endpoint — as well as against the original WH1 strain, Beta and Delta, plus total binding antibodies, were all significantly higher in the teenagers than in the young adults (P < .001) [s1]. Those differences cleared the study's non-inferiority margin, meaning the adolescent response was statistically no worse than the adult benchmark [s1].

The cellular side matched. T-cell responses against BA.1 and Beta rose significantly after the booster (P < .001) [s1]. And the protection looked durable on the timescale measured: antibody levels against the variants tested stayed above their pre-booster baseline through day 336 [s1].

On safety, the adverse events were mostly mild or moderate, dominated by injection-site pain and headache in the four weeks after the shot [s1]. No related serious adverse events were reported [s1].

How to weigh it

The result is encouraging but modest in scope, and the trial's design sets the limits. This was an immunogenicity study: it measured antibody and T-cell levels, not whether boosted adolescents actually caught COVID-19 less often or had milder illness [s1]. Antibody titres are a reasonable stand-in for protection, but they are not the same as counting infections, and the study was not built to do that.

The comparison group also deserves a flag. Rather than randomising teenagers against a contemporaneous arm, the trial measured them against young adults from a previous study [s1]. Historical comparators are weaker than head-to-head randomisation because the groups can differ in timing, prior exposure and circulating variants. The trial was open-label as well, meaning participants and investigators knew who got what — less of a concern for laboratory antibody readings than for subjective outcomes, but worth noting.

The numbers are small for a vaccine study — 240 adolescents overall, with immune responses assessed in fewer than 100 — and, as the authors themselves state, data are still needed in younger children and in specific risk groups before the vaccine's role is settled [s1]. Adolescents in general mount vigorous immune responses, which may be part of why their titres topped the young adults', so the finding should not be read as evidence that the vaccine would perform as well in groups with weaker immune systems, such as younger children or those with chronic illness.

It is also worth setting the result in context. COVID-19 is, for most healthy adolescents, a mild illness, and the case for routine boosting in this age group is itself debated in many countries. A study showing that a particular booster raises antibodies does not settle whether adolescents broadly need boosting at all — only that, where a booster is wanted, this one can do the immunological job in teenagers who were first vaccinated with mRNA.

What the study adds is a reasonable early signal that a protein-based booster can raise strong, lasting immune responses in mRNA-primed adolescents without unexpected safety problems [s1]. For health systems that want a non-mRNA option, or families who prefer one, that is a useful piece of evidence. It is a foundation for the larger, outcome-based trials that would be needed before such a booster becomes a routine recommendation — not a substitute for them.