Humoral immunity under heterologous and homologous COVID-19 vaccination regimens

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease-19 (COVID-19) pandemic. Since its inception in 2019, it has claimed about five million lives and ravaged the global economy. It has been reported that the new SARS-CoV-2 may trigger autoimmunity. Therefore, it is important to investigate whether anti-SARS-CoV2 vaccines induce the formation of autoantibodies and subsequent autoimmunity.

Study: Anti-SARS-CoV-2 vaccination does not induce the formation of autoantibodies, but provides humoral immunity under heterologous and homologous vaccination regimens: Results from a clinical and prospective study among professionals at a German university hospital.  Image credit: ezps / ShutterstockStudy: Anti-SARS-CoV-2 vaccination does not induce the formation of autoantibodies, but provides humoral immunity under heterologous and homologous vaccination regimens: Results from a clinical and prospective study among professionals at a German university hospital. Image credit: ezps / Shutterstock

In a new study, published on medRxiv* preprint server researchers attempted to analyze immune responses after homologous vaccinations or after heterologous vector / mRNA vaccinations for anti-COVID-19 immune responses and autoantibody development.


In half of the COVID-19 cases, the infection shows an invisible course of the disease, which promotes the undetected spread of the virus. In severe cases, COVID-19 affects the skin, kidneys, nervous system and haematological system in addition to the lungs. Such infections often show hyperactivation of neutrophils and excessive production of pro-inflammatory cytokines (similar to patients suffering from autoimmune diseases). Therefore, the immune response in response to SARS-CoV-2 infections is related to autoimmune diseases.

Researchers have reported that COVID-19 patients carrying anti-nuclear antibodies (ANAs), anti-phospholipid antibodies, or anti-SS-A / Ro show more severe results than patients lacking these autoantibodies. In asymptomatic patients, an age-dependent tendency to develop autoantibodies was detected.

By the end of 2020, three COVID-19 vaccines were approved in Germany – BioNTechs Comirnaty and Modernas Spikevax (using mRNA techniques) and AstraZenecas Vaxzevria (using a non-replicating chimpanzee adenovirus). All three vaccines appeared safe and showed significant efficacy in clinical trials. However, no systematic clinical study has yet been published to assess whether COVID-19 vaccination also triggers the production of autoantibodies. To this end, researchers in this study analyzed anti-SARS-CoV2 and autoantibody responses before and after using heterologous and homologous vaccination protocols against COVID-19.

A new study

The participants are from the CoVac study, which started in April 2021 and is an ongoing observational study examining the induction of autoimmunity by COVID-19 vaccination. The participants were from the University Hospital of Magdeburg and the Faculty of Medicine at Otto-von-Guericke University in Magdeburg. They received first-class injections of Spikevax, Vaxzevria, or Comirnaty. Homologous booster doses of Spikevax and Comirnaty were administered after 28 and 41 days, respectively. Participants who received a homologous vaccination with either Spikevax or Comirnaty were combined in the mRNA / mRNA group. The sample consisted of 36% men with a mean age of 36 years for the mRNA / mRNA group, 47 years for the vector / vector group and 38 years for the vector / mRNA group.

Main findings

The research revealed a remarkable difference in SARS-CoV2-specific IgG antibodies when comparing homologous vaccination with mRNA or vector-based vaccines. The number of antibodies produced in the vector / vector group was 10% of the number of antibodies in the mRNA group. In addition, virus neutralization appeared to be significantly less effective in the former group. Researchers thought that serum IgG and / or neutralizing antibodies may not be the best measure of protection. Cellular immunity could contribute to the protection after vaccination and should therefore be considered as a correlate of protection.

The T cell-mediated immunity was also observed to be weaker after Vaxzevria vaccination compared to mRNA vaccination. However, it is currently unknown how strong T cell responses must be to protect against SARS-CoV-2. To solve this problem, more research is needed that analyzes humoral and cellular immunity. If it is proven that the humoral immunity after homologous Vaxzevria immunization is weaker, the third vaccination with an mRNA vaccine may be required.

In the current study, a heterologous vaccination strategy (Vaxzevria followed by an mRNA boost) was as effective in inducing anti-Sp1 IgG antibodies as a homologous mRNA vaccination. However, the pan-antibody response (also including IgA and IgM) was much stronger with heterologous vaccination. The observations presented in this paper, in particular regarding the production of SARS-CoV2-specific IgA, may be of particular interest.

In connection with COVID-19 infections, various reports described the occurrence of autoantibodies and their association with more serious diseases. This study is the first to systematically address this issue. Researchers did not detect induction of autoantibodies after booster vaccination in all three study groups. In women, β2-glycoprotein autoantibodies increased slightly after heterologous vaccination, but remained below the limit.


Researchers analyzed immune responses following homologous (mRNA or vector virus-based) or heterologous (Vector / mRNA) vaccinations for anti-COVID-19 immune responses and the development of autoantibodies. The results indicated that the presence of autoantibodies is a transient event that occasionally accompanies the vaccination, but which has no clinical relevance. However, this result does not hold for a vaccination with new vaccines or repeated vaccinations with the same vaccines. A few limitations of the study relate to the small sample size and short observation period. Future analyzes of larger cohorts are necessary, and such studies should also include a sound control group to improve predictability.

*Important message

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guiding clinical practice / health-related behavior or treated as established information.


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