Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin.

Several studies have suggested the imprinting of SARS-CoV-2 immunity by original immune challenge without addressing the formation of the de novo response to successive antigen exposures. As this is crucial for the development of the original antigenic sin, we assessed the immune response against the mutated epitopes of omicron SARS-CoV-2 after vaccine breakthrough. Our data demonstrate a robust humoral response in thrice-vaccinated individuals following omicron breakthrough which is a recall of vaccine-induced memory. The humoral and memory B cell responses against the altered regions of the omicron surface proteins are impaired. The T cell responses to mutated epitopes of the omicron spike protein are present due to the high cross-reactivity of vaccine-induced T cells rather than the formation of a de novo response. Our findings, therefore, underpin the speculation that the imprinting of SARS-CoV-2 immunity by vaccination may lead to the development of original antigenic sin if future variants overcome the vaccine-induced immunity.

SARS-CoV-2 humoral and cellular immunity following different combinations of vaccination and breakthrough infection.

The elicited anti-SARS-CoV-2 immunity is becoming increasingly complex with individuals receiving a different number of vaccine doses paired with or without recovery from breakthrough infections with different variants. Here we analyze the immunity of individuals that initially received two doses of mRNA vaccine and either received a booster vaccination, recovered from a breakthrough infection, or both. Our data suggest that two vaccine doses and delta breakthrough infection or three vaccine doses and optionally omicron or delta infection provide better B cell immunity than the initial two doses of mRNA vaccine with or without alpha breakthrough infection. A particularly potent B cell response against the currently circulating omicron variant (B. 1.1.529) was observed for thrice vaccinated individuals with omicron breakthrough infection; a 46-fold increase in plasma neutralization compared to two vaccine doses (p < 0.0001). The T cell response after two vaccine doses is not significantly influenced by additional antigen exposures. Of note, individuals with hybrid immunity show better correlated adaptive immune responses compared to those only vaccinated. Taken together, our data provide a detailed insight into SARS-CoV-2 immunity following different antigen exposure scenarios.

Longitudinal monitoring of mRNA-vaccine-induced immunity against SARS-CoV-2.

Background: Worldwide vaccination campaigns significantly reduced mortality caused by SARS-CoV-2 infection and diminished the devastating effects of the pandemic. The first approved vaccines are based on novel mRNA technology and elicit potent immune responses offering high levels of protection from severe disease. Methods: Here we longitudinally assessed adaptive immune responses during a 12-month follow-up period after the initial immunization with 2 doses of mRNA vaccines and after the booster dose in blood and saliva. Results: Our findings demonstrate a rapid waning of the anti-spike IgG titers between months 3 and 6 after the initial vaccination (1.7- and 2.5-fold decrease in plasma and saliva, respectively; P<0.0001). Conversely, the frequency of spike-specific memory B cells increased during this period (2.4-fold increase; P<0.0001) while the frequency of spike-specific CD4+ and CD8+ T cells remained stable for all assessed functions: cytotoxicity, IFNγ, IL-2, and TNFα expression. Booster vaccination significantly improved the antibody response in plasma and saliva, with the most profound changes observed in the neutralization capacity against the currently circulating omicron variant (25.6-fold increase; P<0.0001). The positive effect of booster vaccination was also evident for spike-specific IgG+ memory B cell (2.4-fold increase; P<0.0001) and cytotoxic CD4+ and CD8+ T cell responses (1.7- and 1.9-fold increase respectively; P<0.05). Conclusions: Collectively, our findings offer a detailed insight into the kinetics of adaptive immune response following SARS-CoV-2 vaccination and underline the beneficial effects of a booster vaccination.

Persistent Maintenance of Intermediate Memory B Cells Following SARS-CoV-2 Infection and Vaccination Recall Response.

Robust population-wide immunity will help to curb the SARS-CoV-2 pandemics. To maintain the immunity at protective levels, the quality and persistence of the immune response elicited by infection or vaccination must be determined. We analyzed the dynamics of B cell response during 12 months following SARS-CoV-2 infection on an individual level. In contrast to antibodies, memory B cells specific for the spike (S) protein persisted at high levels throughout the period. These cells efficiently secreted neutralizing antibodies and correlated with IFN-γ-secreting CD4+ T cells. Interestingly, the CD27-CD21+ intermediate memory B cell phenotype was associated with high B cell receptor avidity and the production of neutralizing antibodies. Vaccination of previously infected individuals triggered a recall response enhancing neutralizing antibody and memory B cell levels. Collectively, our findings provide a detailed insight into the longevity of SARS-CoV-2-infection-induced B cell immunity and highlight the importance of vaccination among previously infected. IMPORTANCE To efficiently maintain immunity against SARS-CoV-2 infection, we must first determine the durability of the immune response following infection or vaccination. Here, we demonstrated that, unlike antibodies, virus-specific memory B cells persist at high levels for at least 12 months postinfection and successfully respond to a secondary antigen challenge. Furthermore, we demonstrated that vaccination of previously infected individuals significantly boosters B cell immunity.

Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4+ T cell help.

Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of coronavirus disease 2019 (COVID-19). Compared with severely ill individuals, those who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we identify CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection.

Production of HIV-1 Env-specific antibodies mediating innate immune functions depends on cognate IL-21- secreting CD4+ T cells.

Antibodies with a functional Fc region were previously associated with protection from HIV-1 acquisition and spontaneous suppression of viral replication. Unlike broadly neutralizing antibodies, they are not restricted to neutralizing epitopes and do not require unconventional structural traits to exert their antiviral activity. They, therefore, develop earlier after infection and can be detected in the majority of cases. The conditions under which these antibodies are generated, however, remain largely unknown. Here we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating Fc-dependent innate immune responses, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and NK cell activation, likely depends on help provided by CD4+ T and peripheral T follicular helper (pTfh) cells secreting IL-21. Other proteins, including CD40L, IFNγ, and IL-4/13, involved in crosstalk between B and T cells were linked to the production of antibodies with functional Fc region but only when co-expressed with IL-21. As a potential source of these antibodies, we identified a subset of Env-specific memory B cells known to be expanded in chronic HIV-1 infection. The frequency and level of Blimp-1 expression in Env-specific tissue-like memory B cells (TLM) correlated with the functional CD4+ T cell subsets associated with robust antibody-dependent innate responses. Thus, our data suggest a mechanism responsible for the generation of antibodies with functional Fc region in chronically HIV-1 infected individuals that is based on CD4+ T cell-induced activation of memory B cells.Importance To develop a vaccine or immunotherapy that would cure the HIV-1 infection it is important to identify helper T cells able to mount an efficient antibody response. Here, we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating antibody-dependent innate immune responses likely depends on Env-specific IL-21-secreting CD4+ T and peripheral T follicular helper cells.

Expansion of Stem Cell-Like CD4+ Memory T Cells during Acute HIV-1 Infection Is Linked to Rapid Disease Progression.

Acute HIV-1 infection is characterized by high viremia and massive depletion of CD4+ T cells throughout all tissue compartments. During this time the latent viral reservoir is established but the dynamics of memory CD4+ T cell subset development, their infectability and influence on disease progression during acute HIV-1 infection has not been carefully described. We therefore investigated the dynamics of CD4+ T cell memory populations in the RV217 (ECHO) cohort during the acute phase of infection. Interestingly, while we found only small changes in central or effector memory compartments, we observed a profound expansion of stem cell-like memory CD4+ T cells (SCM) (2.7-fold; P < 0.0001). Furthermore, we demonstrated that the HIV-1 integration and replication preferentially take place in highly differentiated CD4+ T cells such as transitional memory (TM) and effector memory (EM) CD4+ T cells, while naive and less mature memory cells prove to be more resistant. Despite the relatively low frequency of productively infected SCM, we suggest that their quiescent phenotype, increased susceptibility to HIV-1 integration compared to naive cells and extensive expansion make them one of the key players in establishment and persistence of the HIV-1 reservoir. Moreover, the expansion of SCM in acute HIV-1 infection was a result of Fas upregulation on the surface of naive CD4+ T cells. Interestingly, the upregulation of Fas receptor and expansion of SCM in acute HIV-1 infection was associated with the early viral set point and disease progression (rho = 0.47, P = 0.02, and rho = 0.42, P = 0.041, respectively). Taken together, our data demonstrate an expansion of SCM during early acute HIV-1 infection which is associated with disease outcome.IMPORTANCE Understanding the immunopathology of acute HIV-1 infection will help to develop eradication strategies. We demonstrate here that a CD4+ T cell memory subset expands during acute HIV-1 infection, which is associated with disease progression.