IgA Antibodies In Respiratory Tract Can Protect The Unvaccinated Against COVID-19

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A new study by Swedish researchers from University of Gothenburg, Sahlgrenska University Hospital and the Nötkärnan Primary Health Care Center Consortium has found that IgA Antibodies in respiratory tract can protect the unvaccinated against COVID-19.

The study findings were published in the peer reviewed journal: European Journal Of Immunology. https://onlinelibrary.wiley.com/doi/10.1002/eji.202149655

The main goal of this prospective study was to couple the antibody and T-cell responses to SARS-CoV-2 with demographic parameters and clinical features of Covid-19. We chose to study a relatively healthy group of people, primary health care workers naturally exposed to SARS-CoV-2, for a period of 6 months during the Covid-19 pandemic. Our study cohort was representative of health care workers in Sweden, with the exact same mean age of 44, similar female predominance (our study 79% versus 85%) and IgG seroprevalence to SARS-CoV-2 (23% versus 19%) as a larger cross-sectional study conducted among hospital employees in Sweden in the spring 2020 [18]. We identified two main patterns of immune responses to SARS-CoV-2: an IgG-dominated and an IgA-dominated pattern. Only individuals with IgG responses developed T-cell responses to SARS-CoV-2. IgG responsiveness was associated with SARS-CoV-2 PCR positivity and self-reported typical Covid-19 symptoms. In contrast, IgA responsiveness was associated with limited T-cell responses to SARS-CoV-2, autoimmunity, airborne allergy, and not contracting Covid-19.

SARS-CoV-2 IgA-only responders constituted 10% of our cohort which is in line with other studies [819], and 87% of them were already IgA-positive at the start of the study. It is possible that this IgA response constituted cross-reactive IgA antibodies generated in response to other coronaviruses, even though the S1 subunit of the SARS-CoV-2 spike protein used in our antibody tests is less conserved among different Coronavirus strains compared with the S2 subunit [20]. Interestingly, none of the IgA-only responders reported any Covid-19-associated symptoms nor had PCR-confirmed SARS-CoV-2 infection, which implies that SARS-CoV-2-specific IgA-responses may protect against contracting Covid-19. Indeed, one-third of the SARS-CoV-2-specific serum IgA-dominated sera partially neutralized the virus in vitro. It is known that serum IgA is less abundant than serum IgG and not as efficient as serum IgG and mucosal IgA at neutralizing SARS-CoV-2 [9]. The IgA-producing plasma cells that produce serum IgA and mucosal IgA usually originate from the same B-cell clones, but serum IgA is mainly monomeric and consequently of lower avidity compared to mucosal IgA, which is mostly dimeric and predominantly of the IgA2 subclass [21]. The serum IgA we have monitored in this study may be said to be a surrogate marker of nasal IgA, the latter of which confers protection from Covid-19 by preventing virus entry into the body. A limitation of our study is that we did not investigate corresponding nasal IgA antibody levels to SARS-CoV-2 and their neutralizing capacity.

Contrary to the study of Sekine et al., we did not find clear-cut antiviral T-cell responses in person without antibodies to SARS-CoV-2 although we used the same SARS-CoV-2-spike protein peptides to stimulate the T cells in vitro [14]. A likely explanation is that we abstained from adding the T-cell growth factor IL-2 and crosslinking the costimulatory molecules CD28/CD49d in our experimental setup.

Our most interesting finding relating to SARS-CoV-2 T-cell responses was the detection of a unique virus-specific cytotoxic CD4+ T-cell population only harbored by individuals who responded with serum IgG to SARS-CoV-2. The virus-specific T-cell population expressed the activation markers CD25, CD38, and CD69, the inhibitory molecules CTLA-4 and CD279 (PD-1), cytotoxic granzyme B, and the chemokine receptor CCR4 (CD194). Upregulation of inhibitory molecules, such as CTLA-4 and PD-1, by a SARS-CoV-2-specific T-cell subset reflects highly activated effector T cells capable of producing large quantities of granzyme B and IFN-γ [22].

Several of the demographic and clinical parameters revealed in the multivariate analyses to be associated with contracting PCR-verified Covid-19 are well-established risk factors for severe Covid-19 such as male sex and higher BMI. However, none of our study participants required hospitalization for Covid-19. Nevertheless, male sex is a risk factor for most infectious diseases [23]. We identified female sex, airborne allergy, and smoking to be associated with protection from Covid-19, which is in line with previous findings. A Spanish registry study covering close to half a million individuals showed that the risk of contracting Covid-19 was lower in asthmatics with an odds ratio of 0.74 (95% CI: 0.71–0.77) [24]. Although it is clear that smoking is a risk factor for the severity of Covid-19, early studies reported an underrepresentation of smokers among patients hospitalized for Covid-19 [25]. Perhaps smoking-induced inflammation of the upper respiratory mucosa provides low-degree protection against transmission of viral infection.

Our study attempted to cover a gap in knowledge regarding how immunity to SARS-CoV-2 develops over time in a relatively healthy group of adults, and how this relates to the risk of becoming infected, demographic, and clinical risk factors, and immune correlates of protection from contracting Covid-19. The vast majority of published studies on Covid-19 have been cross-sectional and/or focused on hospitalized patients with severe disease. Our key findings were that (1) every tenth person had a potentially neutralizing IgA response which was associated with not contracting Covid-19; (2) an IgG response was strongly associated with T-cell responsiveness to SARS-CoV-2 and having contracted Covid-19, and (3) there was scant evidence of T-cell responsiveness to SARS-CoV-2 among seronegative individuals.

Our study cohort was representative of health care workers in Sweden, with the exact same mean age of 44, similar female predominance (our study 79% versus 85%) and IgG seroprevalence to SARS-CoV-2 (23% versus 19%) as a larger cross-sectional study conducted among hospital employees in Sweden in the spring 2020 [18].

We identified two main patterns of immune responses to SARS-CoV-2: an IgG-dominated and an IgA-dominated pattern. Only individuals with IgG responses developed T-cell responses to SARS-CoV-2.

IgG responsiveness was associated with SARS-CoV-2 PCR positivity and self-reported typical Covid-19 symptoms. In contrast, IgA responsiveness was associated with limited T-cell responses to SARS-CoV-2, autoimmunity, airborne allergy, and not contracting Covid-19.

SARS-CoV-2 IgA-only responders constituted 10% of our cohort which is in line with other studies [8, 19], and 87% of them were already IgA-positive at the start of the study. It is possible that this IgA response constituted cross-reactive IgA antibodies generated in response to other coronaviruses, even though the S1 subunit of the SARS-CoV-2 spike protein used in our antibody tests is less conserved among different Coronavirus strains compared with the S2 subunit [20].

Interestingly, none of the IgA-only responders reported any Covid-19-associated symptoms nor had PCR-confirmed SARS-CoV-2 infection, which implies that SARS-CoV-2-specific IgA-responses may protect against contracting Covid-19.

Indeed, one-third of the SARS-CoV-2-specific serum IgA-dominated sera partially neutralized the virus in vitro. It is known that serum IgA is less abundant than serum IgG and not as efficient as serum IgG and mucosal IgA at neutralizing SARS-CoV-2 [9].

The IgA-producing plasma cells that produce serum IgA and mucosal IgA usually originate from the same B-cell clones, but serum IgA is mainly monomeric and consequently of lower avidity compared to mucosal IgA, which is mostly dimeric and predominantly of the IgA2 subclass [21].

The serum IgA we have monitored in this study may be said to be a surrogate marker of nasal IgA, the latter of which confers protection from Covid-19 by preventing virus entry into the body. A limitation of our study is that we did not investigate corresponding nasal IgA antibody levels to SARS-CoV-2 and their neutralizing capacity.

Contrary to the study of Sekine et al., we did not find clear-cut antiviral T-cell responses in person without antibodies to SARS-CoV-2 although we used the same SARS-CoV-2-spike protein peptides to stimulate the T cells in vitro [14]. A likely explanation is that we abstained from adding the T-cell growth factor IL-2 and crosslinking the costimulatory molecules CD28/CD49d in our experimental setup.

Our most interesting finding relating to SARS-CoV-2 T-cell responses was the detection of a unique virus-specific cytotoxic CD4+ T-cell population only harbored by individuals who responded with serum IgG to SARS-CoV-2. The virus-specific T-cell population expressed the activation markers CD25, CD38, and CD69, the inhibitory molecules CTLA-4 and CD279 (PD-1), cytotoxic granzyme B, and the chemokine receptor CCR4 (CD194). Upregulation of inhibitory molecules, such as CTLA-4 and PD-1, by a SARS-CoV-2-specific T-cell subset reflects highly activated effector T cells capable of producing large quantities of granzyme B and IFN-γ [22].

Several of the demographic and clinical parameters revealed in the multivariate analyses to be associated with contracting PCR-verified Covid-19 are well-established risk factors for severe Covid-19 such as male sex and higher BMI. However, none of our study participants required hospitalization for Covid-19. Nevertheless, male sex is a risk factor for most infectious diseases [23].

We identified female sex, airborne allergy, and smoking to be associated with protection from Covid-19, which is in line with previous findings. A Spanish registry study covering close to half a million individuals showed that the risk of contracting Covid-19 was lower in asthmatics with an odds ratio of 0.74 (95% CI: 0.71–0.77) [24].

Although it is clear that smoking is a risk factor for the severity of Covid-19, early studies reported an underrepresentation of smokers among patients hospitalized for Covid-19 [25]. Perhaps smoking-induced inflammation of the upper respiratory mucosa provides low-degree protection against transmission of viral infection.

Our study attempted to cover a gap in knowledge regarding how immunity to SARS-CoV-2 develops over time in a relatively healthy group of adults, and how this relates to the risk of becoming infected, demographic, and clinical risk factors, and immune correlates of protection from contracting Covid-19.

The vast majority of published studies on Covid-19 have been cross-sectional and/or focused on hospitalized patients with severe disease. Our key findings were that (1) every tenth person had a potentially neutralizing IgA response which was associated with not contracting Covid-19; (2) an IgG response was strongly associated with T-cell responsiveness to SARS-CoV-2 and having contracted Covid-19, and (3) there was scant evidence of T-cell responsiveness to SARS-CoV-2 among seronegative individuals.

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