Fact check: What are the most recent studies on vaccine efficacy in preventing COVID-19 fatalities?

1. Why the headlines differ: symptomatic infection versus fatality prevention

Studies often report differing endpoints—infection, symptomatic disease, hospitalization, and death—which drives variation in headline efficacy. Meta-analyses published in 2024 emphasized that bivalent boosters provided roughly 30–50% effectiveness against infection or symptomatic Omicron subvariants but noted greater effectiveness against severe clinical outcomes ^{[2] [1]}. A phase 3 trial of a tetravalent protein vaccine reported 69.4% efficacy against symptomatic infection at day 7, but the trial focused on symptomatic endpoints and reported no vaccine-related deaths, which does not directly quantify fatality reduction at population scale ^[3]. Comparing these metrics without noting endpoints can mislead about death prevention.

2. Consolidating the evidence: what meta-analyses report about preventing deaths

Systematic reviews and meta-analyses through mid-2024 consistently find that boosters and multivalent vaccines substantially reduce severe outcomes, which are proxies for fatality prevention in population studies. A 28-study meta-analysis covering over 55 million individuals concluded bivalent boosters provided 30–50% VE against infection with Omicron subvariants and higher effectiveness against severe outcomes ^[2]. Another review found bivalent vaccines’ absolute effectiveness versus unvaccinated of about 53.5% for any symptomatic infection and relative gains over earlier monovalent doses, while noting better performance for preventing serious disease ^[1]. These aggregated findings indicate more robust protection against hospitalization and death than against mild infection.

3. New trials and formulations: how SCTV01E and tetravalent approaches change the landscape

A randomized phase 3 trial of the SCTV01E tetravalent protein vaccine reported 69.4% efficacy against symptomatic SARS‑CoV‑2 infection seven days after vaccination and no vaccine-related serious adverse events or deaths ^[3]. While promising, this single-trial result does not directly quantify mortality reduction across diverse populations and variants. The trial’s favorable safety profile strengthens the case for broader use, but mortality impacts typically require larger real-world datasets and longer follow-up. Therefore, randomized efficacy against symptomatic disease complements but does not replace large observational studies when estimating death prevention.

4. Variant-adapted vaccines: XBB and the elderly—who benefits most?

More recent 2025 network meta-analyses indicate that XBB 1.5–adapted vaccines maintain effectiveness against hospitalization, and comparisons across mRNA formulations showed similar overall protection with some evidence favoring BNT162b2 in elderly subgroups ^[4]. This suggests that updating antigens to match circulating subvariants sustains protection against severe outcomes. Observational and meta-analytic work in clinically vulnerable populations also shows that poor antibody responses correlate with higher risks of breakthrough infection, hospitalization, and death, emphasizing that vaccine-induced immunogenicity remains a key predictor of fatality risk reduction in high-risk groups ^[5].

5. Gaps and limitations: observational biases and endpoint heterogeneity

Interpretation must account for limitations: many meta-analyses combine heterogeneous study designs, differing comparator groups (unvaccinated, monovalent-primed), and variable follow-up windows, producing wide confidence intervals and potential selection biases ^{[2] [1]}. Trials like SCTV01E offer internal validity but may not reflect variant evolution or real-world uptake ^[3]. Network meta-analyses of variant-adapted vaccines synthesize large datasets but can be influenced by differential healthcare access, prior infection prevalence, and age distributions that affect observed fatality reductions ^{[4] [5]}. These factors can both under- and over-estimate mortality benefit.

6. Practical takeaways for policy and clinicians: boost strategies matter for death prevention

Aggregated evidence supports that updated boosters and multivalent vaccines reduce severe COVID-19 and thereby lower fatalities, especially among older adults and immunocompromised patients who show weaker antibody responses ^{[2] [5]}. Policy decisions should prioritize timely booster campaigns with variant-adapted formulations for high-risk populations, coupled with serologic or clinical monitoring of vulnerable groups. However, efficacy against symptomatic infection varies, so expectations should be framed around preventing hospitalization and death rather than eliminating transmission ^{[1] [3]}.

7. Where researchers should focus next to answer mortality questions definitively

To quantify vaccine effects on fatalities more precisely, studies need harmonized endpoints (all-cause and COVID-specific mortality), randomized effectiveness where feasible, and large real-world cohorts with variant sequencing and immunogenicity data. Comparative effectiveness of XBB-adapted versus prior boosters in elderly subgroups requires longer follow-up and stratified analyses to separate vaccine formulation effects from confounders like prior infection ^{[4] [5]}. Continued meta-analytic updates as new trials and surveillance data accumulate will be essential to refine estimates of mortality prevention.