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Are there high-quality studies showing minimal or no effectiveness of primary 2-dose COVID-19 vaccination against symptomatic infection with XBB.1.5 and later subvariants?
Executive summary
High-quality, peer-reviewed and large real-world studies show that the primary 2-dose COVID-19 vaccine series provides little durable protection against symptomatic infection caused by XBB.1.5-era and later Omicron subvariants, but it still reduces severe outcomes; analyses focus on updated (XBB.1.5- or later–adapted) booster doses rather than the original 2-dose primary series (not found in current reporting). Available large observational and review papers report modest-to-low effectiveness against infection (VE ~16–45% waning quickly) while showing stronger protection against hospitalization (pooled VE ~41–56% in older adults) for updated boosters [1] [2] [3].
1. What the literature actually measures — boosters, not just the original 2-dose series
Most high-quality studies and reviews in the current record evaluate effectiveness of updated XBB.1.5-adapted or later booster vaccines and population-level protection after more recent vaccine doses; they do not primarily report on the two-dose primary series by itself in the XBB.1.5-era. For example, CDC network analyses and systematic reviews assess the incremental protection of 2023–2024 and 2024–2025 updated doses (monovalent XBB.1.5 and later), not the original 2-dose primary regimen alone [3] [2]. Available sources do not mention standalone VE estimates for an isolated 2-dose primary series against symptomatic XBB.1.5 infection.
2. Infection (symptomatic) protection: modest and short-lived in real-world studies
Real-world cohort analyses reported in the press and academic summaries indicate modest effectiveness against infection that wanes rapidly. One institutional summary of 2024–2025 vaccines found peak effectiveness against infection around ~44.7% at four weeks falling to ~35.5% by 10 weeks and ~16.7% by 20 weeks [1]. Those figures relate to updated formulations and indicate that protection against symptomatic infection with Omicron-lineage subvariants is limited and declines quickly, which implies the original 2-dose series—without recent boosting—would perform worse, but that assertion is not directly documented in the cited material [1].
3. Severe disease and hospitalization: consistent benefit, especially with updated boosters
High-quality syntheses and large cohort/case‑control studies pooled in a New England Journal of Medicine review found that among adults 65+, mRNA XBB.1.5-adapted vaccines had pooled vaccine effectiveness of about 56% (95% CI, 51–60) against hospitalization; other case–control studies showed VE against hospitalization in the 41–54% range [2]. CDC VISION/IVY test‑negative analyses likewise concluded that receipt of 2024–2025 vaccine doses provided additional protection against ED/UC encounters and hospitalizations compared with not receiving the updated dose [3]. These findings emphasize retained protection against severe outcomes even as protection against symptomatic infection erodes [2] [3].
4. Study quality and what “high-quality” means here
The strongest evidence in the provided set comes from large test‑negative designs, multi‑site cohort and case–control studies, and systematic reviews/meta-analyses published or summarized in high‑tier outlets (CDC MMWR, NEJM review). Those designs are standard for vaccine effectiveness in real-world settings and detect modest-to-moderate VE against infection and clearer benefit against severe disease for updated vaccines [3] [2]. However, the examined studies generally assess the effect of updated booster doses and mixed prior immunity (vaccination plus prior infection), so isolating the contribution of a two-dose primary series alone against contemporary XBB-lineage symptomatic infection is not possible from these sources (not found in current reporting).
5. Alternative interpretations and implicit agendas
Public-health agencies (CDC, ACIP) and academic reviews frame these data to support updated vaccination strategies because they show preserved protection against severe outcomes and incremental benefit of updated boosters [3] [2]. Vaccine manufacturers emphasize immunogenicity and trial toplines for new formulations [4]. Critics who point to low VE against infection often highlight rapid waning and immune escape; the reviewed sources acknowledge that mismatch with circulating lineages and viral evolution reduce protection against symptomatic infection but still document benefits for severe disease [1] [2]. Each group has incentives: public-health bodies to maintain uptake and reduce hospital burden, and manufacturers to demonstrate product value [3] [4].
6. Bottom line for your question
If your specific question asks whether high‑quality studies show “minimal or no effectiveness” of a primary 2‑dose series against symptomatic XBB.1.5 and later subvariants, the available reporting does show low and rapidly waning effectiveness against symptomatic infection for vaccines not recently updated or boosted, but the provided studies focus on updated booster effectiveness rather than isolated 2‑dose primary-series estimates — therefore standalone two‑dose VE against symptomatic XBB.1.5-era infection is not directly reported in these sources [1] [3] [2]. All cited analyses agree that protection against hospitalization and severe disease remains materially better, particularly after updated boosters [2] [3].