Safety, reactogenicity, and immunogenicity of the BNT and half-m1273 mRNA COVID-19 vaccines given as a fourth dose booster

In a recent study posted to Preprints with The Lancet*, researchers evaluated the immunogenicity of Pfizer’s BNT162b2 and Moderna’s messenger ribonucleic acid (mRNA-1273) vaccines offered as the fourth dose against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Study: Immunogenicity and Reactogenicity of BNT162b2 and mRNA1273 COVID-19 Vaccines Given as Fourth Dose Boosters in the COV-BOOST Randomised Trial Following Two Doses of ChAdOx1 nCov-19 or BNT162b2 and a Third Dose of BNT162b2. Image Credit: Tanya Dol/Shutterstock


Several countries began administering booster shots of coronavirus disease 2019 (COVID-19) vaccines in addition to the two-dose primary series. The third vaccination significantly boosted both the cellular and humoral immune responses. In light of the waning immunity post-third vaccination, Germany and Israel commenced the fourth vaccination, i.e., the second booster shot. The United Kingdom (UK) started the same for vulnerable groups in April 2022.

Nevertheless, the timing, quantity, effectiveness of the third vaccination, and clinical need for the fourth vaccination remain uncertain. Hence, there is a pressing need to inform policymakers about booster vaccination.

About the study

The researchers of the present study investigated the reactogenicity, safety, and immunogenicity of the fourth vaccination, which was administered eight months post-third vaccination. COV-BOOST is a randomized controlled trial of the third vaccination for COVID-19 among those who received the BNT162b2 or ChAdOx1 vaccines in the primary series.

Eligible participants were those who completed booster vaccination with the BNT162b2 vaccine in the COV-BOOST trial. Participants were randomized 1:1 to receive the BNT162b2 or mRNA-1273 vaccine as a fourth shot. An immunology sub-cohort was created to collect samples 14 days (D14) after the fourth dose. Statisticians randomized and stratified participants based on the primary vaccination, age, study site, and general or immunology cohorts.

Reactogenicity and safety were evaluated by the frequency of solicited adverse events (AEs) within seven days of the fourth vaccination, unsolicited AEs within 28 days (D28), and medically-attended AEs for up to three months. Immunogenicity outcomes such as immunoglobulin G (IgG) responses against SARS-CoV-2 spike (S) protein were evaluated for all subjects. Cellular immune responses were examined using ELISpot assays for those in the immunology cohort. Immunogenicity analyses compared the IgG and T cell responses at D14 after the fourth dose relative to D28 after the third dose.


Around 215 subjects were offered a third dose in June 2021; 166 received a fourth in January 2022. Previously, 88 participants received two ChAdOx1 vaccines in the primary series and a BNT162b2 vaccine as the booster (ChAd/ChAd/BNT), and the remaining received all three doses of BNT162b2 vaccine (BNT/BNT/BNT). All participants were randomized equally for the BNT162b2 or mRNA-1273 booster shots. Overall, 133 participants were selected for the immunogenicity analysis, with 67 receiving the mRNA-1273 vaccine and 66 receiving the BNT162b2 vaccine.

The most common AE was local pain for both the fourth-dose arms. Headache, fatigue, muscle ache, and malaise were the most commonly reported systemic AEs. Sixteen AEs were reported post-fourth dose with the BNT162b2 vaccine and 18 post-fourth doses with the mRNA-1273 vaccine. The anti-S IgG titers were 23,325 enzyme-linked immunosorbent assay units (ELU) per milliliter (ml) at D28 post the third dose, which increased to 37,460 ELU/ml at D14 after the fourth BNT162b dose exhibiting a fold change of 1.59.

Similarly, the fourth vaccination with mRNA1273 dose increased the anti-S IgG titers by 2.19-fold from 25,317 ELU/ml at D28 post-third dose to 54,936 ELU/ml at D14 post-fourth dose. A significant decay of IgG titers was observed after the third vaccination until before the fourth vaccination causing a high boosting effect post-fourth dose.

Among participants with available cellular immunology data, T cell responses at D14 post-fourth dose were similar to D28 post-third dose for participants in these series – ChAd/ChAd/BNT/BNT, BNT/BNT/BNT/BNT, and ChAd/ChAd/BNT/mRNA-1273. T cell responses were higher after the fourth dose among BNT/BNT/BNT/mRNA-1273 vaccinees than post-third dose levels. The authors observed a significant decay of T cell responses posts the third dose until before the fourth dose, boosting cellular responses significantly post-fourth dose.


The study findings showed that the fourth dose of either mRNA-1273 or BNT162b2 vaccine could substantially boost the cellular and humoral responses with higher anti-S IgG titers after the fourth dose than the post-third vaccination for both vaccines. The fold difference of anti-S titers after the fourth dose ranged between 11 and 20 compared to that post-third dose, possibly because the vaccines are highly immunogenic, and the boosting effect is evaluated using a low baseline level. However, some participants had high humoral and cellular levels pre-fourth dose and did not exhibit a high fold difference after the fourth dose.

The study limitations include the smaller sample size in each group besides recruiting only BNT162b2 vaccinees, due to which the potential benefit of heterologous vaccination could not be adequately investigated. Notably, only RNA-based vaccines were examined for the fourth vaccination, the availability of which is limited in low and middle-income countries. In conclusion, the authors noted that the fourth vaccine dose is well tolerated and effectively increases cellular and humoral immunity against SARS-CoV-2.

*Important notice

Preprints with The Lancet publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Munro, A. et al. (2022) "Immunogenicity and Reactogenicity of BNT162b2 and mRNA1273 COVID-19 Vaccines Given as Fourth Dose Boosters in the COV-BOOST Randomised Trial Following Two Doses of ChAdOx1 nCov-19 or BNT162b2 and a Third Dose of BNT162b2", SSRN Electronic Journal. doi: 10.2139/ssrn.4076824.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, covid-19, Enzyme, Fatigue, Frequency, Headache, immunity, Immunoglobulin, Immunology, Muscle, Pain, Protein, Respiratory, Ribonucleic Acid, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Vaccine

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Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.

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