Emerging heterologous mRNA-based booster strategies within the COVID-19 vaccine landscape

The paper addresses how COVID-19 vaccination strategies should evolve from primary schedules toward booster approaches in response to waning immunity and the emergence of SARS-CoV-2 variants of concern (VoCs) such as delta and omicron. Heterologous or mix-and-match booster regimens—where the booster differs from the primary vaccine—may simplify logistics, help manage supply constraints, and potentially optimize breadth and durability of protection. The authors focus on mRNA-based platforms because of their adaptability and demonstrated efficacy and discuss considerations (practicality, supply, regimen selection, effectiveness, safety, and variant targeting). The review aims to synthesize clinical and real-world evidence on the immunogenicity, effectiveness, and safety of heterologous regimens including at least one mRNA vaccine, to inform optimal booster choices globally, especially for high-risk groups.

The review summarizes the evolving COVID-19 vaccine landscape across platforms (mRNA, adenoviral vector, protein subunit, inactivated virus) and regulatory contexts in the US and Europe. It compiles evidence that mRNA vaccines are highly effective against symptomatic and severe disease but that effectiveness wanes over time and is reduced against some VoCs, particularly omicron. Initial booster work focused on homologous regimens; however, multiple studies now evaluate heterologous primary and booster schedules, including COV-BOOST (UK), Com-COV2 (UK), ARNCOMBI (France), SWITCH (Netherlands), NIH DMID (US), HKSH (Hong Kong), PRIBIVAC (Singapore), and others. Real-world observational studies from Sweden, England, Spain, Chile, Germany, and the US complement trial data, particularly during delta and omicron waves. Collectively, published findings suggest heterologous regimens with mRNA components often match or exceed homologous schedules in immunogenicity and effectiveness, with acceptable safety.

A PubMed search identified clinical trials and observational studies on COVID-19 vaccination regimens from January 1, 2021 to June 29, 2022 (English only), yielding 595 articles. Inclusion criteria: studies describing heterologous vaccine regimens and at least one mRNA vaccine (mRNA-1273 or BNT162b2). Exclusions: reviews; studies in special populations (e.g., immunocompromised); non–peer-reviewed articles (with exceptions for relevant preprints and one CDC MMWR), studies of non-mRNA vaccines only; observational studies with small populations (~<100,000); and observational data collected before December 2021. Sixteen articles (covering 15 studies) were included: eight clinical trials and seven observational studies. Additionally, three clinical and one observational study were identified outside PubMed via ClinicalTrials.gov, pipeline knowledge, and related searches. Most studies involved adults ≥18 years. The review first compared immunogenicity (humoral and cellular), then summarized reactogenicity and safety, and finally examined effectiveness, especially against VoCs. Key trials included NIH DMID (US), COV-BOOST (UK), Com-COV2 (UK), ARNCOMBI (France), SWITCH (Netherlands), HKSH (Hong Kong), PRIBIVAC (Singapore), and early studies of monovalent/bivalent variant-adapted boosters (e.g., mRNA-1273.211, mRNA-1273.214).

• Heterologous primary regimens:
  • Com-COV2: Heterologous ChAd-Ox1.S→mRNA-1273 or BNT162b2→mRNA-1273 was non-inferior to homologous schedules; anti-spike IgG at Day 28 post–dose 2 was highest for ChAd-Ox1.S/mRNA-1273 and BNT162b2/mRNA-1273; ChAd-Ox1.S/mRNA-1273 yielded the strongest cellular response.
  • ARNCOMBI: Heterologous BNT162b2/mRNA-1273 was non-inferior to homologous mRNA regimens.
  • SWITCH: After Ad26.COV2.S priming, dose 2 with mRNA-1273 induced higher S-specific antibody binding than BNT162b2.
• Heterologous booster immunogenicity:
  • NIH DMID: At ~Day 29 post-boost, anti-spike IgG and pseudovirus neutralization were highest when mRNA-1273 was used as booster, for both homologous and heterologous regimens. Durable CD4+ responses across priming vaccines; more durable CD8+ responses when Ad26.COV2.S was used in the regimen (as prime or booster).
  • COV-BOOST: Heterologous mRNA-1273 boosting after ChAd-Ox1.S or BNT162b2 priming produced higher anti-spike IgG at Day 28 than homologous boosting; robust T-cell responses across boosters, with ChAd-Ox1.S prime plus mRNA-1273 boost eliciting strong T-cell responses. Fourth-dose mRNA boosters further increased humoral and cellular immunity.
• Effectiveness against VoCs (observational and trial data):
  • Sweden cohort (delta period): Heterologous ChAd-Ox1.S/mRNA-1273 VE 79% and ChAd-Ox1.S/BNT162b2 VE 67% against symptomatic COVID-19, both higher than homologous ChAd-Ox1.S/ChAd-Ox1.S (50%).
  • England test-negative analyses: mRNA boosters after ChAd-Ox1.S or BNT162b2 increased protection against delta and omicron symptomatic disease, though waning occurred within 5–10 weeks; lower VE against omicron than delta.
  • US VISION network (omicron period): VE for emergency/urgent care visits was 83% for 3-dose mRNA regimens, 79% for Ad26.COV2.S primary plus mRNA booster, and 54% for homologous Ad26.COV2.S. VE against hospitalization: 90% (3-dose mRNA), 78% (Ad26.COV2.S→mRNA), 67% (Ad26.COV2.S→Ad26.COV2.S).
  • Spain (omicron period): mRNA boosters moderately effective in preventing infection (~51%), highest in those primed with ChAd-Ox1.S (59%) and mRNA-1273 (55%).
  • Germany cohort: Highest neutralization against alpha/beta/gamma for ChAd-Ox1.S/mRNA-1273 (87%/85%/71%), then ChAd-Ox1.S/BNT162b2 (82%/70%/55%); mRNA vaccines elicited faster and higher humoral/cellular responses than ChAd-Ox1.S.
  • Trials/VoC targeting: COV-BOOST showed comparable or improved responses to VoCs vs WT for mRNA boosters; PRIBIVAC (≥60 years) heterologous mRNA-1273 booster showed stronger neutralization vs homologous BNT162b2 (84% vs 73%; p=0.0073) including against omicron.
• Variant-adapted mRNA boosters in development:
  • mRNA-1273.211 (beta-containing bivalent): Higher neutralizing titers vs mRNA-1273 against beta, delta, and omicron at 4 weeks; maintained superiority for beta and omicron at 6 months.
  • mRNA-1273.214 (omicron-containing bivalent): ~5.4-fold rise in neutralization against BA.4/BA.5 at 1 month post-boost in all participants; 6.3-fold in seronegative subset; safety/reactogenicity similar to 50 μg mRNA-1273 booster.
  • Pfizer-BioNTech omicron-adapted vaccines (monovalent/bivalent) elicited higher responses vs homologous BNT162b2 boost and were generally well tolerated.
• Safety/reactogenicity:
  • Across trials (NIH DMID, COV-BOOST, Com-COV2, ARNCOMBI, SWITCH), both homologous and heterologous boosters were well tolerated; common short-lived events within 7 days included injection-site pain, malaise, headache, myalgia, fatigue.
  • mRNA-1273 often showed higher reactogenicity than BNT162b2 (more local pain/redness and fatigue) but within acceptable ranges; higher reactogenicity also noted when mRNA or Ad26.COV2.S was given after two ChAd-Ox1.S doses.
  • Rare myocarditis/pericarditis has been reported with mRNA vaccines, with elevated risk primarily among males aged 18–24 years; overall rates not higher than expected in most groups.
• Practical considerations:
  • Heterologous mRNA-based boosting supports supply flexibility, may increase breadth/durability of protection, and can be tailored to circulating VoCs; refrigerator-stable candidates (e.g., mRNA-1283) are in development to ease storage constraints.

Findings indicate that heterologous booster strategies incorporating mRNA vaccines, particularly mRNA-1273, generally produce equal or superior humoral and cellular immunity compared with homologous schedules, and provide strong real-world effectiveness against symptomatic disease and severe outcomes during variant waves. The addition of an adenoviral vector component within heterologous regimens may augment CD8+ T-cell responses, potentially enhancing durability. Although mRNA-1273 may be more reactogenic than BNT162b2, adverse events are transient and acceptable relative to the benefits of enhanced immunogenicity and protection. Evidence supports at least one booster for the general population (additional doses for older or immunocompromised individuals), with mRNA-based boosters improving protection against delta and omicron, though protection against symptomatic omicron infection wanes over weeks. Variant-adapted bivalent mRNA boosters show promising immunogenicity against emerging subvariants and may further optimize booster strategies. Implementation of heterologous mRNA-based boosting can also address logistical challenges and region-specific primary regimens, potentially simplifying mass vaccination as VoCs evolve.

Heterologous booster strategies after a primary COVID-19 vaccine series are safe, effective, and pragmatic for preventing severe COVID-19 outcomes. mRNA platforms offer rapid adaptability to emerging variants, enabling timely deployment of updated boosters. Optimal heterologous priming and boosting should consider previously administered primary regimens and circulating VoCs. Ongoing clinical trials and real-world studies, including evaluations of bivalent/variant-adapted mRNA boosters and next-generation formulations with improved storage, will refine recommendations and enhance global coverage and protection.

Most available clinical data derive from healthy adult populations, with limited evidence in specific subgroups (e.g., immunocompromised, pediatric). There is no universally accepted correlate of protection; humoral and cellular measures are proxies. Real-world data primarily reflect periods of delta and early omicron (BA.1/BA.2) dominance; evidence against newer subvariants (e.g., BA.4/BA.5 and beyond) is still emerging. Several studies were not powered to detect differences in reactogenicity/safety across regimens. Protection against asymptomatic infection is incompletely characterized. Long-term durability and the relationship between waning antibodies and clinical protection, as well as optimal booster intervals and scheduling, require further study.