Clinical Scorecard: Comparing Booster Vaccine Strategies: A Longitudinal Study of Humoral Immune Response to Omicron in a Malaysian Population

At a Glance

Key Highlights

• The study evaluated longitudinal humoral immune responses following 5 COVID-19 booster regimens, including 3 homologous and 2 heterologous combinations.

• Of 332 participants included in 24-week follow-up, 268 completed follow-up and 190 were included in the longitudinal immunogenicity analysis after exclusions.

• Heterologous booster regimens, particularly inactivated virus–mRNA vaccination, produced higher and more sustained anti-S IgG and anti-RBD responses than the homologous inactivated virus–inactivated virus regimen.

• At week 24, anti-S IgG and anti-RBD seropositivity remained 100% in the inactivated virus–mRNA group, compared with 15.63% and 18.75%, respectively, in the inactivated virus–inactivated virus group.

• Omicron neutralization at week 24 was 95.92% with inactivated virus–mRNA boosting, 83.87% with viral vector–mRNA boosting, and 9.38% with inactivated virus–inactivated virus boosting.

• Time to new SARS-CoV-2 infection differed significantly across the 5 vaccine groups.

• The study protocol was approved by the human ethics committee of Manipal University College Malaysia.

Guideline-Based Recommendations

Diagnosis

• New SARS-CoV-2 infections during follow-up were confirmed using quantitative reverse transcription polymerase chain reaction testing targeting the viral N and RdRP genes.

Management

• Participants received homologous mRNA-mRNA, viral vector–viral vector, or inactivated virus–inactivated virus boosters, or heterologous inactivated virus–mRNA or viral vector–mRNA boosters based on individual choice.

• The study findings support the immunologic rationale for mix-and-match booster approaches in individuals initially immunized with inactivated-virus or viral-vector vaccines.

Monitoring & Follow-up

• Blood samples were obtained before booster vaccination and at weeks 2, 4, 8, 12, 16, and 24.

• Plasma was assessed for anti-S IgG and anti-RBD antibodies.

• The seropositivity threshold was 5 U/mL, corresponding to 109 binding antibody units/mL.

• Omicron neutralization was assessed using a surrogate virus neutralization test.

• Participants who developed new SARS-CoV-2 infection during follow-up were excluded from subsequent primary immunogenicity analyses because infection-associated immune responses could confound assessment of booster-related antibody kinetics.

Risks

• Individuals with severe adverse effects requiring hospitalization were excluded.

• Individuals with autoimmune disease were excluded.

• An unvaccinated control group could not be included because COVID-19 vaccination was mandatory for federal government employees and healthcare professionals.

Patient & Prescribing Data

Participants were adults older than 18 years who had completed a primary COVID-19 vaccination regimen and had not had COVID-19 within the previous 3 months.

The study evaluated booster combinations involving mRNA, inactivated-virus, and viral-vector vaccines. Of the 190 participants included in the longitudinal immunogenicity analysis, 52 received mRNA-mRNA vaccination, 32 received inactivated virus–inactivated virus vaccination, 26 received viral vector–viral vector vaccination, 49 received inactivated virus–mRNA vaccination, and 31 received viral vector–mRNA vaccination.

Clinical Best Practices

• The study found that humoral immune responses varied substantially by booster regimen over the 24-week follow-up.

• Heterologous mRNA boosting, particularly following an inactivated-virus primary regimen, was associated with stronger and more sustained humoral immune responses than homologous inactivated-virus boosting.

• The authors state that the findings support the immunologic rationale for mix-and-match booster approaches in individuals initially immunized with inactivated-virus or viral-vector vaccines.

• The authors also note that antibody dynamics alone cannot fully predict protection against emerging Omicron subvariants.

Related Resources & Content

Mixing versus matching booster vaccines: Longitudinal humoral immune kinetics against Omicron in a Malaysian cohort — Ashwathy Varadarajan Thundakattil, Rekha Prabhu, Girish Prabhu, Muthuvel Mani, Somsubhra De, Htoo Htoo Kyaw Soe, Charlotte Patrick Arjunan, Sumandeep Kaur Chahl, Debban A/L Ramesh, Ng Jian Chen, Soh Pei Qi, Jaayshree A/P Prakash, Nikhytha A/P Chandran, Mila Nu Nu Htay, Sabyasachi Das — International Journal of Infectious Diseases — 2026.

Emerging heterologous mRNA-based booster strategies within the COVID-19 vaccine landscape — Das R, Hyer RN, Burton P, Miller JM, Kuter BJ — Hum Vaccin Immunother — 2023.

Heterologous SARS-CoV-2 spike protein booster elicits durable and broad antibody responses against the receptor-binding domain — Takano T, Sato T, Kotaki R, Moriyama S, Fukushi S, Shinoda M, et al — Nat Commun — 2023.

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant — Garcia-Beltran WF, St Denis KJ, Hoelzemer A, Lam EC, Nitido AD, Sheehan ML, et al — Cell — 2022.

Homologous and heterologous Covid-19 booster vaccinations — Atmar RL, Lyke KE, Deming ME, Jackson LA, Branche AR, El Sahly HM, et al — N Engl J Med — 2022.

Real-world effectiveness of homologous and heterologous BNT162b2, CoronaVac, and AZD1222 booster vaccination against Delta and Omicron SARS-CoV-2 infection — Suah JL, Tng BH, Tok PSK, Husin M, Thevananthan T, Peariasamy KM, et al — Emerg Microbes Infect — 2022.

Heterologous versus homologous COVID-19 booster vaccinations for adults: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials — Asante MA, Michelsen ME, Balakumar MM, Kumburegama B, Sharifan A, Thomsen AR, et al — BMC Med — 2024.