Impact of Previous Common Human Coronavirus Exposure on SARS-CoV-2-Specific T-Cell and Memory B-Cell Response after mRNA-Based Vaccination.

OBJECTIVE: T-cell responses against SARS-CoV-2 are observed in unexposed individuals, attributed to previous common human coronavirus (HCoV) infections. We evaluated the evolution of this T-cell cross-reactive response and the specific memory B-cells (MBCs) after the SARS-CoV-2 mRNA-based vaccination and its impact on incident SARS-CoV-2 infections. METHODS: This was a longitudinal study of 149 healthcare workers (HCWs) that included 85 unexposed individuals that were subdivided according to previous T-cell cross-reactivity, who were compared to 64 convalescent HCWs. Changes in specific T-cell response and memory B-cell (MBC) levels were compared at baseline and after two doses of the SARS-CoV-2 mRNA-based vaccine. RESULTS: A cross-reactive T-cell response was found in 59% of unexposed individuals before vaccination. Antibodies against HKU1 positively correlated with OC43 and 229E antibodies. Spike-specific MBCs was scarce in unexposed HCWs regardless of the presence of baseline T-cell cross-reactivity. After vaccination, 92% and 96% of unexposed HCWs with cross-reactive T-cells had CD4+ and CD8+ T-cell responses to the spike protein, respectively. Similar results to that were found in convalescents (83% and 92%, respectively). Contrarily, higher than that which was observed in unexposed individuals without T-cell cross-reactivity showed lower CD4+ and CD8+ T-cell responses (73% in both cases, p = 0.03). Nevertheless, previous cross-reactive T-cell response was not associated with higher levels of MBCs after vaccination in unexposed HCWs. During a follow-up of 434 days (IQR, 339-495) after vaccination, 49 HCWs (33%) became infected, with a significant positive correlation between spike-specific MBC levels and isotypes IgG+ and IgA+ after vaccination and a longer time to get infected. Interestingly, T-cell cross-reactivity did not reduce the time to vaccine breakthrough infections. CONCLUSION: While pre-existing T-cell cross-reactivity enhances the T-cell response after vaccination, it does not increase SARS-CoV-2-specific MBC levels in the absence of previous infection. Overall, the level of specific MBCs determines the time to breakthrough infections, regardless of the presence of T-cell cross-reactivity.

Impact of SARS-CoV-2-specific memory B cells on the immune response after mRNA-based Comirnaty vaccine in seronegative health care workers.

Purpose: To analyze the impact of SARS-COV-2-specific memory B cells (MBC) on the immune response after two doses of mRNA-based Comirnaty COVID-19 vaccine in seronegative health care workers. This study is seeking a rationale for boosting vaccines. Methods: Longitudinal study including 31 seronegative health care workers with undetectable specific MBCs (IgG-MBC- group), 24 seronegative with detectable specific MBCs (IgG-MBC+ group), and 24 seropositive with detectable specific MBCs (IgG+MBC+ group). The level of antibodies that inhibit ACE2-RBD interaction, and anti-Spike IgG, IgA, and IgM antibodies was quantified by ELISA. In addition, specific memory B and T cells were quantified by flow cytometry. Results: The level of specific MBCs, and isotypes, in the IgG-MBC- group was lower compared to that found in IgG-MBC+ (p = 0.0001) and IgG+MBC+ (p < 0.0001) groups, respectively. ACE2-RBD neutralizing antibodies and anti-S IgG antibodies were at lower levels in the IgG-MBC-group after the vaccine. Specific MBCs directly correlated with specific CD4+ T cells (although not significant, p = 0.065), while no correlation was found with specific CD8+ T cells (p = 0.156) after the vaccine. In parallel, ACE2-RBD neutralizing antibodies only positively correlated with specific CD4+ T cells (p = 0.034). Conclusion: IgG-MBC- individuals showed the worst humoral and cellular responses, both in frequency and magnitude, after vaccination. Individuals whose antibodies wane and become undetectable after a given period of time post vaccination and show no specific MBCs are less protected and hence are good candidates for boosting vaccine. On the other hand, seronegative individuals with specific MBC showed faster and higher responses compared to the IgG-MBC- group.

Risk of SARS-CoV-2 Reinfections in a Prospective Inception Cohort Study: Impact of COVID-19 Vaccination.

The risk of reinfection could be related to the initial SARS-CoV-2 clinical presentation, but there are no data about the risk change after SARS-CoV-2 vaccination. We evaluated the rate of reinfection in an inception cohort study of 4943 health care workers (HCWs) according to symptoms and serologic results during March-May 2020. Incidence rates (IR) and IR ratios (IRR) before and after SARS-CoV-2 vaccination were determined by adjusting Poisson models. Overall, 1005 HCWs (20.3%) referred COVID-19 suggestive symptoms during the first surge of disease, and 33.5% and 55% presented a positive PCR or serology result, respectively. Meanwhile, 13% of asymptomatic HCWs had specific antibodies. During a follow up of 3422.2 person-years before vaccination, the rate of reinfection among seropositive individuals was 81% lower for those who were symptomatic compared with those who were asymptomatic (IRR of 0.19; 95% CI, 0.05-0.67; p = 0.003). During the 3100 person-years period after vaccination, an overall 74% decrease in the rate of infection was observed (IRR of 0.26; 95% CI, 0.21-0.32; p < 0.001), with a significant 83% and 70% decrease in seropositive and seronegative HCWs, respectively. In conclusion, the risk of SARS-CoV-2 reinfections is closely related to the clinical and serological presentation of COVID-19. COVID-19 vaccination further decreases the risk of reinfection more markedly among seropositive.

Pre-existing T cell immunity determines the frequency and magnitude of cellular immune response to two doses of mRNA vaccine against SARS-CoV-2.

Little is known about the factors associated with lack of T-cell response to mRNA vaccines against SARS-CoV-2. In a prospective cohort of 61 health care workers (HCWs), 21% and 16% after the first dose of mRNA BNT162b vaccine, and 12% and 7% after the second dose, showed lack of CD4+ and CD8+ T-cell response, respectively. Pre-existing T-cell immunity, due to past infection (46%) or cross-reactive cellular response (26%), was significantly associated with T-cell response in frequency (CD4+ T-cell, 100% vs 82% after two doses; p = 0.049) and in the magnitude of T-cell response during follow up. Furthermore, baseline CD4+ T-cell correlated positively with the titer of specific IgG-antibodies after first and second vaccine dose. Our data demonstrate that cross-reactive T-cells correlate with a better cellular response as well as an enhanced humoral response, and we confirm the close correlation of humoral and cellular response after mRNA vaccination.

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection induces elevated levels of inflammatory cytokines, which are mainly produced by the innate response to the virus. The role of NK cells, which are potent producers of IFN-γ and cytotoxicity, has not been sufficiently studied in the setting of SARS-CoV-2 infection. We confirmed a different distribution of NK cell subsets in hospitalized COVID-19 patients despite their NK cell deficiency. The impairment of this innate defense is mainly focused on the cytotoxic capacity of the CD56dim NK cells. On the one hand, we found an expansion of the CD56dimCD16neg NK subset, lower cytotoxic capacities, and high frequencies of inhibitory 2DL1 and 2DL1/S1 KIR receptors in COVID-19 patients. On the other hand, the depletion of CD56dimCD16dim/bright NK cell subsets, high cytotoxic capacities, and high frequencies of inhibitory 2DL1 KIR receptors were found in COVID-19 patients. In contrast, no differences in the distribution of CD56bright NK cell subsets were found in this study. These alterations in the distribution and phenotype of NK cells might enhance the impairment of this crucial innate line of defense during COVID-19 infection.

Cellular Responses to Membrane and Nucleocapsid Viral Proteins Are Also Boosted After SARS-CoV-2 Spike mRNA Vaccination in Individuals With Either Past Infection or Cross-Reactivity.

SARS-CoV-2 spike mRNA vaccines have shown remarkable clinical efficacy in the general population, although the nature of T-cell priming is not fully understood. We performed longitudinal spike-, membrane-, and nucleocapsid-specific T-cell analysis in individuals with past infection and infection-naïve individuals with cross-reactivity. We found an additional enhancement of T-cell response to the structural membrane (M) and nucleocapsid (N) SARS-CoV-2 proteins after mRNA vaccine in these individuals. Thus, despite the spike-specific response, we found that the first dose of the vaccine boosted a significant CD8 cell response to M and N proteins, whereas no cellular response to those proteins was found in infection-naïve individuals without pre-existing cross-reactivity who were tested for eventual asymptomatic infection. These findings highlight the additional benefit of mRNA vaccines as broad boosters of cellular responses to different viral epitopes in these individuals and suggest extended protection to other viral variants.

BNT162b2 mRNA COVID-19 vaccine Reactogenicity: The key role of immunity.

We examined the impact of pre-existing SARS-CoV-2-specific cellular immunity on BNT162b2 mRNA COVID-19 vaccine reactogenicity. Of 96 healthcare workers (HCWs), 76% reported any vaccine reaction (first dose: 70%, second dose: 67%), none of which was severe. Following first dose, systemic reactions were significantly more frequent among HCWs with past infection than in infection-naïve individuals, and among HCWs with pre-existing cellular immunity than in those without it. The rate of systemic reactions after second dose was 1.7 and 2.0-times higher than after first dose among infection-naïve HCWs and those without pre-existing cellular immunity, respectively. Levels of SARS-CoV-2-specific T-cells before vaccination were higher in HCWs with systemic reactions after the first dose than in those without them. BNT162b2 vaccine reactogenicity after first dose is attributable to pre-existing cellular immunity elicited by prior COVID-19 or cross-reactivity. Reactogenicity following second dose suggests an immunity-boosting effect. Overall, these data may reduce negative attitudes towards COVID-19 vaccines. Study Registration. The study was registered on clinicaltrials.gov, NCT04402827.

T-cell response after first dose of BNT162b2 SARS-CoV-2 vaccine among healthcare workers with previous infection or cross-reactive immunity.

OBJECTIVES: Antibody response to the first dose of BNT162b2 SARS-CoV-2 is greater in COVID-19-convalescent than in infection-naïve individuals. However, there are no data about T-cell response in individuals with pre-existing cellular immunity. METHODS: We evaluated T-cell responses in parallel with SARS-CoV-2 antibody level after first dose of BNT162b2 vaccine in 23 infection-naïve and 27 convalescent healthcare workers (HCWs) previously included in a study about humoral and T-cell immunity. RESULTS: Overall, the antibody response was lower in the infection-naïve group than in convalescent individuals (18 895 vs 662.7 AU mL-1, P < 0.001), and intermediate but significantly lower in convalescent HCWs with previous negative serology (25 174 vs 1793 AU mL-1; P = 0.015). Indeed, anti-spike IgG titres after the first dose correlated with baseline anti-nucleocapsid IgG titres (rho = 0.689; P < 0.001). Pre-existing T-cell immunity was observed in 78% of convalescent and 65% of the infection-naïve HCWs. T-cell response after the first dose of the vaccine was observed in nearly all the cases with pre-existing T-cell immunity, reaching 94% in convalescent HCWs and 93% in those with cross-reactive T cells. It was lower in the infection-naïve group (50%; P = 0.087) and in convalescent HCWs with negative serology (56%; P = 0.085). Notably, systemic reactogenicity after vaccination was mainly observed in those with pre-existing T-cell immunity (P = 0.051). CONCLUSION: Here, we report that the first dose of BTN162b2 elicits a similar S-specific T-cell response in cases of either past infection or cross-reactive T cells, but lower in the rest of infection-naïve individuals and in convalescent HCWs who have lost detectable specific antibodies during follow-up.

SARS CoV-2 infections in healthcare workers with a pre-existing T-cell response: a prospective cohort study.

OBJECTIVE: T-cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are observed in unexposed individuals. We evaluated the impact of this pre-existing cellular response on incident SARS-CoV-2 infections. METHODS: This was a follow-up study of 38 seronegative healthcare workers (HCWs) with previous evaluation of CD8+ and CD4+ T-cell responses after stimulation with SARS-CoV-2 structural proteins. Infection was considered in the presence of a positive RT-PCR test and/or confirmed seroconversion. RESULTS: Twenty of the 38 HCWs included (53%) had a previous specific CD8+ T-cell response to peptides encompassing the spike protein (S) in 13 (34%), the membrane (M) in 17 (45%), or/and the nucleocapsid (N) in three (8%). During a follow-up of 189 days (interquartile range (IQR) 172-195), 11 HCWs (29%) had an RT-PCR-positive test (n = 9) or seroconverted (n = 2). Median duration of symptoms was 2 days (IQR 0-7), and time to negative RT-PCR was 9 days (IQR 4-10). Notably, six incident infections (55%) occurred in HCWs with a pre-existing T-cell response (30% of those with a cellular response), who showed a significantly lower duration of symptoms (three were asymptomatic). Three of the six HCWs having a previous T-cell response continued to test seronegative. All the infected patients developed a robust T-cell response to different structural SARS-CoV-2 proteins, especially to protein S (91%). CONCLUSION: A pre-existing T-cell response does not seem to reduce incident SARS-CoV-2 infections, but it may contribute to asymptomatic or mild disease, rapid viral clearance and differences in seroconversion.