In a recent study posted to the medRxiv* preprint server, researchers evaluated the cellular and humoral immunity following heterologous and homologous coronavirus disease 2019 (COVID-19) immunization regimens for up to five months. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines evaluated were BNT162b2 and ChAdOx1 nCoV-19.

Study: Dynamics of humoral and cellular immune responses after homologous and heterologous SARS-CoV-2 vaccination with ChAdOx1 nCoV-19 and BNT162b2. Image Credit: Tero Vesalainen/Shutterstock
Study: Dynamics of humoral and cellular immune responses after homologous and heterologous SARS-CoV-2 vaccination with ChAdOx1 nCoV-19 and BNT162b2. Image Credit: Tero Vesalainen/Shutterstock


The most significant tool for combating the COVID-19 pandemic is vaccines. Many nations advise a heterologous vaccination strategy containing messenger ribonucleic acid (mRNA) vaccines such as BNT162b2 for the second dose. This was due to unusual severe adverse effects following the adenoviral ChAdOx1 nCoV-19 vaccination.

The authors of the present work previously conducted a PubMed search employing “heterologous vaccination” and “SARS-CoV-2” as search phrases with no time constraints and discovered 247 articles. Only a small percentage of papers featured direct comparisons of patient populations who received either a homologous or heterologous COVID-19 immunization regimen. The great majority of them only focused on short-term immunogenicity following vaccination. As a result, little is understood about the sustained preservation of immunity via heterologous vaccination relative to homologous vaccination.

Taken together, although the COVID-19 vaccines elicit SARS-CoV-2-specific T cell and antibody responses, it is still unclear how long the vaccine-stimulated immunity lasts after heterologous and homologous vaccination regimens. 

About the study

In the current study, the researchers compared the dynamics of cellular and humoral immune responses up to five months following heterologous or homologous vaccination with the COVID-19 vaccines: BNT162b2 (BNT) and ChAdOx1–nCoV–19 (ChAd). The study consisted of 473 patients among three vaccination cohorts (ChAd-ChAd, BNT-BNT, and ChAd-BNT). 

While the BNT and ChAd vaccines’ homologous groups primarily comprised healthcare professionals, the heterologous cohort was not restricted to any specific professionals. The subjects’ peripheral blood mononuclear cells (PBMCs) and serum samples were procured from three independent research centers at various timeframes beginning from after the second dose vaccination until five months. Furthermore, comparative analyses were conducted at two independent research sites in Germany. Additionally, T cell and humoral immune responses were investigated thoroughly.

Results and discussions

The results indicated that all BNT and ChAd vaccination regimens demonstrated drastically lower neutralizing capacity towards the SARS-CoV-2 Delta and Omicron variants of concern (VOCs). The BNT-BNT and ChAd-BNT groups had greater neutralizing antibody responses against the SARS-CoV-2 wildtype (WT) strain and VOCs than the ChAd-ChAd cohort.

As the neutralizing antibody titers were closely related to infection protection, vaccination efficacy (VE) against the SARS-CoV-2 VOC infection has declined considerably over time. VE was observed to be equivalent for ChAd-BNT and BNT-BNT vaccination schedules following three to six months of the second dose immunization yet lower for the ChAd-ChAd regimen.

Both the BNT-BNT and the ChAd-BNT cohorts’ antibody avidity rose modestly from the initial to the latter timestep, possibly indicating continuing B-cell maturation. The high avidity of antibodies generated by the heterologous ChAd-BNT vaccination explains why they exhibit a better neutralization capability against SARS-CoV-2 VOCs in both research locations.

The variation in the gap between the first and second vaccination doses, which was between 21 and 23 days for homologous BNT-BNT vaccinees and 63 days for ChAd-BNT vaccinees, might be one cause for the variable affinity development of memory B cells. Furthermore, the length of antigen presentation in the germinal centers may vary following mRNA or vector vaccination.

Following heterologous and homologous vaccination, the majority of the participants maintained spike(S)-reactive T cells at the late time point. Longitudinal frequency assessment in each vaccinee revealed that long-standing quantities of the S-specific T cells were at a level achieved after the initial vaccination. This was observed at two separate research centers.

According to the study outcome, the heterologous vaccination strategy was continuously non-inferior and, in some cases, statistically considerably better than the homologous BNT vaccination. A priming dose of ChAd has previously been demonstrated to generate a more robust T cell response than the primary BNT vaccination, but this was no longer the case following a subsequent dose of the BNT vaccine. Nonetheless, this might imply that the heterologous vaccination regimen’s overall advantage in cellular and humoral immunogenicity was due to a more robust initial immune response.

Polyfunctional CD4 T cells were present four months following the second dose in all vaccination schedules. However, this was less obvious in CD8 T cells, most likely due to the varied recognition of CD8 epitopes in the 15mer peptides utilized for antigenic stimulation. These findings suggest that heterologous vaccination, similar to homologous immunization, may induce long-term persistence of polyfunctional S-specific T cells. Further, this probably imparts protective immunity.


The study findings indicated that the antibody responses against SARS-CoV-2 decreased considerably following COVID-19 vaccination, regardless of the immunization schedule. The BNT vaccine neutralized the SARS-CoV-2 variants, including the Omicron or Delta VOCs, better in the heterologous regimen than in the homologous regimen. In addition, the BNT homologous and heterologous vaccination schedules elicited long-standing antibody-mediated immunity versus the ChAd homologous regimen. Notably, the T cell responses were less waning regardless of the immunization schedule. 

Collectively, the present work demonstrated that heterologous immunization with BNT and ChAd COVID-19 vaccines effectively induced long-lasting cellular and humoral immune protection against SARS-CoV-2. Further suggestions about the timing, choice, necessity of additional vaccines, and public health policy will require a better knowledge of the immunity generated by specific vaccination regimens.

*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.


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