Study says COVID mRNA-based vaccines best for booster vaccination

The immune response against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent that triggered the onset of the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to be the focus of intensive research around the world. The neutralization capacity, as well as durability and breadth, of the immune response, is key to its ability to protect against reinfection, especially as new variants continue to emerge and vaccination coverage continues to expand.

A new study published on the preprint server medRxiv* looks at the adaptive immune response to COVID-19 vaccines, wherein the authors compare heterologous to homologous immunization in terms of the elicited humoral and cellular components.

Study: Interdependencies Between Cellular and Humoral Immune Responses in Heterologous and Homologous SARS-Cov-2 Vaccination. Image Credit: Marc Bruxelle /


Vaccines that immunize against SARS-CoV-2 produce antibodies to the spike receptor-binding domain (RBD) and neutralizing antibodies that prevent virus-receptor attachment. The observed diminution in antibody-mediated protection over time, as demonstrated by reduced antibody titers and increased reports of breakthrough infections, emphasizes the need to optimize vaccination schedules.

Another compelling reason for such research is the fact that the AstraZeneca vaccine ChAdOx1-S was initially rolled out in Europe, with a large proportion of people receiving the first dose. As reports of a small but significant risk of cerebral venous thrombosis began to emerge, many countries subsequently restricted the administration of this vaccine to older people who were at low risk for this complication.

However, these announcements meant that those who had received the first dose already but were not eligible for the second dose were at risk for SARS-CoV-2 infection. To overcome this, heterologous vaccination was proposed, with the Pfizer/BioNTech BNT162b2 vaccine being given as the booster following an initial priming dose of the AstraZeneca vaccine. The chief obstacle at the time was the lack of data on the immunogenicity and safety of such a regimen.

This has since been overcome by new research; however, the need to understand corresponding cellular responses still remains. In addition, the titers of individual antibody subtypes in this situation remain to be studied.

About the study

In the current study, researchers carried out a prospective observational cohort study (COV-ADAPT) on over 400 healthcare workers, all of whom received two doses of either ChAdOx1-S (AstraZeneca/AZ) or Pfizer/BioNTech BNT162b2 vaccines. The mean age was 35 years, with a male to female ratio of 3:1.

There were three groups included in the current study, one which had received AZ/AZ vaccine doses, the second AZ/BNT162b2, and the last BNT162b2/BNT162b2. The first group was somewhat older than the others since they had been targeted first for vaccination as the most high-risk group.

The researchers, therefore, compensated for differences in age and sex when evaluating the immune response. Vaccine recipients were evaluated for the humoral response that included measurements of anti-SARS-CoV-2 immunoglobulin G (IgG) to the RBD, neutralizing antibodies, and avidity.

In addition, the cellular response was assessed in terms of the spike-induced release of interferon (IFN)-γ by T-cells. Both immune responses were tested up to two weeks before, and at 2-12 weeks after the second dose.

Study findings

The initial dose with the AZ vaccine generated lower anti-RBD IgG responses than the BNT162b2 at the first time point T1, at 70 and 226 BAU/mL, respectively. Both vaccines produced comparable T-cell activation responses.

At the second time point T2, the AZ/AZ regimen generated a markedly lower antibody response, with the anti-RBD IgG titer being only 413 as compared to 2,400 and 3,200 with an AZ/BNT162b2 and BNT162b2/BNT162b2 regimen, respectively.

Thus, both groups that used BNT162b2 as the booster had high effective anti-RBD titers.

When either the ChAdOx1-S or BNT162b2 vaccines were used as the prime dose of vaccine, no significant difference in T-cell activation was reported at about 700 and 1,277, respectively. With an AZ homologous booster dose, no increase was observed in T-cell activation. However, the BNT162b2 booster produced effective activation, regardless of which vaccine was given as the priming dose.

The greatest response appeared to depend on the time between the booster dose and the time of the assay for the AZ/BNT162b2 regimen, but none of the others.

Spike RBD IgG titers and spike-directed IFN-γ T-cell responses were found to be positively associated with each other at both time points overall. This was due to the major associations seen in the AZ/BNT162b2 and AZ/AZ groups at T1 but not T2, with no correlation observable in the BNT162b2/BNT162b2 group at either time point.

Moreover, the higher the T-cell activation response at T1, the better the antibody response at T2 for the BNT162b2 booster groups, regardless of the type of priming vaccine.

All three regimens were found to elicit neutralizing antibodies and increased antibody avidity. The largest increase was from the first to the second dose in the AZ/AZ and AZ/BNT162b2 groups.     


This is the first study to examine the interactions between cell-mediated and antibody-mediated immunity after a heterologous immunization series using an AstraZeneca priming dose and the BNT162b2 booster dose, to protect against COVID-19.

The findings suggest that individuals with a robust initial response developed strong humoral and cellular immune responses after booster immunization.”

It is also important to note that all three regimens produced the same effect on neutralization capacity, perhaps because it was already high after the priming dose. The greater period over which immunity remained active for the AZ/AZ vaccination compared to the BNT162b2/BNT162b2 group could be the result of the transcription of the spike DNA delivered by the adenovirus vectored DNA in the AZ vaccine as compared to the short lifespan of messenger ribonucleic acid (RNA) that is associated with lower overall exposure to the spike protein.

In future research, this difference in the immune response with variation in the vaccination protocol must be considered an important factor in population-level vaccine programs. Secondly, a poor antibody response will not be compensated for by a strong cellular immune response. The homologous BNT162b2/BNT162b2 vaccine regimen produces a good immune response that was better than that due to the homologous AZ/AZ vaccine or the heterologous AZ/BNT162b2 regimen.

In view of the increased humoral and cellular immunity obtained with the use of the Pfizer-BioNTech messenger RNA (mRNA) vaccine, these vaccines should be used to boost the immune response following a priming dose with the AstraZeneca vaccine. This is all the more important if the response to the initial dose of the vaccine was poor. Humoral responses predict the cellular responses; however, a low antibody-mediated response is not compensated for by high cell-mediated responses.

*Important notice

medRxiv publishes 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:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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