Primary responses to SARS-CoV-2 in COVID-19 naïve vaccinees

In a recent study posted to the bioRxiv* preprint server, a team of researchers evaluated primary responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve vaccinees, as well as secondary responses in the SARS-CoV-2-infected vaccinees and observed a clear set of differences in their clinical symptoms, antibody levels, and cellular and mucosal immune responses.

Study: Mucosal and systemic responses to SARS-CoV-2 vaccination in infection naïve and experienced individuals. Image Credit: Lightspring/ShutterstockStudy: Mucosal and systemic responses to SARS-CoV-2 vaccination in infection naïve and experienced individuals. Image Credit: Lightspring/Shutterstock

Data from other research studies showing a decrease in the durability of protection from SARS-CoV-2 after vaccination make it imperative for the global medical community to develop an in-depth understanding of these primary and secondary immune responses against SARS-CoV-2.

Study design

The authors of this serosurvey comprehensively evaluated immune responses in SARS-CoV-2-naïve and SARS-CoV-2-infected vaccinees. From a total of 3816 health care workers (HCW) who enrolled for this survey, 67 volunteers had to fill in two questionnaires. The first questionnaire asked for details of their coronavirus disease 2019 (COVID-19) history, and the second questionnaire enquired about the post-vaccination symptoms.

All the volunteers had taken two doses of either the Pfizer BNT162b2 or the Moderna mRNA-1273 vaccine. The two vaccines shared similarities in design and mode of action; however, the dosage of Moderna was 3.3 times the dosage of the Pfizer vaccine. The vaccinated individuals were sub-divided into Ab negative group, Asymptomatic group, and Symptomatic group. Blood samples for testing were taken at day 0 (or baseline), 7, 10, and 14 days after the first dose of vaccine, and 0, 7, 10, 14, and 28 days and 3 and 10 months after the second dose of vaccine.


After the first dose of vaccine, individuals in both the Asymptomatic and Symptomatic groups (SARS-CoV-2-infected groups) had more systemic symptoms such as fever, chills, fatigue, myalgia, headache, etc., compared to those in the Ab negative group (SARS-CoV-2-naïve group). After the second dose of vaccine, the Ab negative group showed increased symptoms.

In the context of cellular responses, before vaccination, of the two SARS-CoV-2-infected groups, the Symptomatic group had slightly higher baseline levels than the Asymptomatic group. The cellular responses in all three groups reached a peak at day 14 after the first vaccine dose. However, no changes were observed in any of the three groups on day 14 after the second dose of the vaccine. Two weeks after the second dose of Moderna, the SARS-CoV-2-naïve group showed elevated responses across all CD4, cTFH, and CD8 assays, while the Symptomatic group showed elevated cTFH response only.

The study documented plasma levels of antibodies across all the groups. Peaking titers were observed in the Symptomatic and Asymptomatic groups by Day 7 after the first vaccination explaining why SARS-CoV-2-infected vaccinees appear to have less reinfection than SARS-CoV-2-naïve vaccines. Also, two weeks after vaccination, both these groups showed higher IgA and IgG responses at all time points measured, and up to 10 months in the case of IgG. The neutralizing antibody titers against the Wuhan and Delta variants of SARS-CoV-2 were close to 10 times higher in the two SARS-CoV-2-infected groups.

However, the Ab negative group, whose individuals were mounting a primary response, showed higher IgM responses and peak titers only after the second vaccination. The study continued for 10 months after the second vaccination. Interestingly, there was no difference in the slope of the decline of antibody levels between the three groups. Nevertheless, the IgG antibody levels in the SARS-CoV-2-infected groups remained higher at each time point.

The nasal mucosa is the first contact site between SARS-CoV-2 and humans. The study results of non-vaccine-specific nasal mucosal responses have shown that IgA and IgG are abundant in the nasal mucosa, with IgA being more predominant. Most of the IgA is present on-site in the form of dimers, but IgG produced in the bone marrow/lymph nodes arrives at the site by transcytosis process involving the FcRn receptor (systemic circulation).

The study results showed that before vaccination, S-specific IgG/IgA ratio in the SARS-CoV-2-infected individuals was much lower in the nose than blood, suggesting local IgA production. After vaccination, IgG/IgA ratio skewed to as much as 100:1, indicating IgG titers increased in the nasal mucosa and surpassed the IgA titers, and attained similar concentrations as measured in plasma, where IgG levels outpaced IgA.


The study outlines key differences in the responses to SARS-CoV-2 vaccination depending on previous exposure to the virus. Subsequently, SARS-CoV-2-infected vaccinees had higher binding and neutralization titers throughout the study. Similarly, their IgG and IgA levels at mucosal sites were higher, enhancing the protective efficacy of the mRNA vaccines.

These lingering differences between the SARS-CoV-2-infected and SARS-CoV-2-naïve groups were observed up to 10 months post-vaccination, suggesting that additional strategies, such as giving booster doses to the SARS-CoV-2-naïve vaccinees. However, it is not yet clear whether booster doses will equalize the antibody response and peak titers among all the groups in this study and if they will alleviate or narrow down the immunological differences observed between them.

To conclude, the data generated in this study can help inform the number of vaccinations and booster doses needed for enhanced protection in both SARS-CoV-2-infected and SARS-CoV-2-naïve vaccinees.

*Important notice

bioRxiv 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:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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