A phase 3 clinical trial has tested a new RNA vaccine against influenza

The new mRNA influenza vaccine evaluated in this phase 3 trial represents a significant advance over traditional platforms. In a season dominated by subtype A, the vaccine showed a 34.5% improvement in relative efficacy compared to a standard inactivated vaccine and generated higher antibody titers for H1N1 and H3N2, as well as a significantly more robust T-cell response, which could translate into broader and potentially longer-lasting protection.

However, the absence of circulating influenza B virus during the study and the fact that immunological non-inferiority against B lineages was not met raise some questions about its performance in seasons with different viral compositions.

The immunological cost of this improved performance is greater reactogenicity, as previously observed with the mRNA platform. The frequency of local and systemic reactions was higher, with fever occurring in 5.6% of those vaccinated with mRNA compared to 1.7% with the conventional vaccine, although most were mild and transient. This can have a considerable impact on public acceptance and tolerability.

Looking ahead, mRNA technology opens a promising path toward more agile and potentially more universal influenza vaccines. Its ability to induce potent cellular responses and to be rapidly updated against new lineages could change the paradigm of seasonal influenza campaigns. However, it is still necessary to demonstrate its year-to-year consistency, its actual efficacy against subtype B viruses, and its performance in higher-risk populations not included in the trial (the elderly, pregnant women, and immunocompromised individuals).

This is an important, but still preliminary, step toward a new generation of more flexible influenza vaccines with more ambitious effectiveness.

It is a very well done study, showing superiority of the mRNA vaccine versus the conventional vaccine, but with, perhaps not surprising, increased reactogenicity. It would have been better if it was compared side by side with the baculo HA vaccine, licensed in several countries, which is thought to be superior too to the conventional vaccine. It is also unclear how the vaccine compare to the enhanced conventional vaccines for the elderly, adjuvanted or high dose, in order to see whether it represents a clear advantage.

It is a great outcome for pandemic preparedness, as it suggests that H5 mRNA vaccines will work, having them more possibilities for getting quick vaccines in the case of an H5 pandemic.

The article presents a high-quality scientific study, published in one of the most prestigious biomedical journals, The New England Journal of Medicine, renowned for disseminating clinical studies of high therapeutic relevance. In this case, the efficacy of a quadrivalent messenger RNA (mRNA) vaccine, developed by Pfizer, is evaluated in a phase 3 clinical trial in humans. The formulation includes four mRNA sequences that encode the hemagglutinins of the H1N1 and H3N2 influenza A viruses, as well as the Yamagata and Victoria lineages of influenza B.

The efficacy of this vaccine is compared to that of the currently used conventional vaccine, which contains purified hemagglutinins from the same four viruses. The study analyzes the vaccine's ability to prevent infection, induce specific antibodies against seasonal influenza viruses, and stimulate T-cell-mediated cellular immunity, in addition to quantifying adverse effects of the vaccination.

The results are promising, although limited to a population aged 18 to 64, a group with a lower risk of severe influenza complications compared to older adults, especially those over 75. The study is part of the technological competition between companies like Moderna and Pfizer to develop more effective flu vaccines.

The mRNA-based formulation shows greater reactogenicity, meaning a higher frequency of mild or moderate symptoms after vaccination, compared to the conventional vaccine. No conclusive data are provided on its ability to prevent severe acute respiratory illness or on its long-term efficacy (more than one year), although the advance in protection against influenza A is acknowledged, while limitations in coverage against influenza B and in tolerability are noted.

The proposed vaccine offers a significant improvement in the immune response, both humoral (antibodies) and cellular (T lymphocytes), compared to the inactivated vaccines currently used in seasonal campaigns. Although protection against infection still has room for improvement, the mRNA platform allows for greater flexibility and speed in vaccine design and production, as well as the introduction and modification of antigens. This represents a strategic advantage over conventional formulations, which require more complex and lengthy processes.

[Regarding potential limitations] The higher reactogenicity observed could affect public acceptance, especially in the context of annual vaccinations. Furthermore, the study does not provide data on efficacy in preventing severe disease or on its performance in at-risk groups such as young children and the elderly. The lack of this data limits the extrapolation of results to vulnerable populations. An improvement in efficacy would also be expected, but this needs to be proven.

If reactogenicity can be reduced without compromising efficacy, this vaccine could become a viable alternative to current formulations. Additionally, the inclusion of mRNA encoding other viral proteins, such as neuraminidase, could broaden immunological coverage and improve the protective profile of future versions.

This study compares an RNA vaccine against influenza A (A/H3N2), A (A/H1N1), B (B/Yamagata), and B (B/Victoria) strains with a commercially available vaccine containing inactivated viruses of these four influenza strains.

The study demonstrates that the RNA vaccine does not induce a weaker immune response than the conventional vaccine and provides superior short-term protection. However, it induces greater reactogenicity, with effects such as fatigue, fever, headache, and injection site pain being more pronounced than those observed with the control vaccine.

A large number of participants were included in this phase III trial, but the efficacy results for both vaccines in preventing infection were modest, with a relative efficacy of 35.8% at seven days post-vaccination and similar efficacy at 14 days post-vaccination. Figure 1 shows a relative vaccine efficacy of 34.5%, although higher for the RNA vaccine than for the inactivated virus vaccine. In the analysis at the end of the flu season, the relative efficacy of the vaccine was 28.7%, which is a very modest efficacy.

Studies of cellular response were carried out with analysis of interferon-gamma production by both CD4+ and CD8+ lymphocytes. A greater response was observed than that achieved by the inactivated viruses of the commercial vaccine, especially for T helper lymphocytes, while for CD8+ lymphocytes, two A strains did not induce a good CD8+ cellular response.

Detailed analysis:

1. The study of the immune response is short-term, with a period of 130 days to analyze cases of infection, but the study of the immune response and the neutralizing capacity of hemagglutinin was performed soon after inoculation of the vaccine.
2. Of the four strains studied (two of A and two of B), Yamagata has not been circulating for several years, and, in fact, the WHO recommended in September 2023 not including it in vaccines, recommending that trivalent vaccines be produced with only 3 strains (2 of A and one of B).
3. It is interesting to note that the response obtained against strain B (B/Victoria) in relation to hemagglutinin neutralization capacity and seroconversion is very low with the mRNA vaccine, compared to the commercial control vaccine.
4. Volunteers aged 18-64 years, with a more robust immune system than those over 65, who are the target population for this type of vaccine, have been studied. The limited protection induced by this vaccine indicates that either the sequences included in the vaccine did not correspond to the strains that caused the infection, or that the vaccine does not elicit a good immune response.
5. This new mRNA vaccine has been compared to another commercial vaccine, not a placebo, which leads to studying relative rather than absolute efficacy, as the authors themselves indicate as a limitation of their study. However, it is very interesting to have a comparative study of two vaccines.
6. This type of vaccine can be produced in less time than traditional vaccines, but it should focus on the most vulnerable target population. A relative efficacy of 28.7% has considerable room for improvement.
7. The responses in children, another population highly vulnerable to influenza, have not been studied either.
8. The greater reactogenicity of a vaccine that would foreseeably need to be administered annually, depending on the changing circulating strains, could be a problem for public acceptance.