Adjuvanted SARS-CoV-2 Spike Protein Elicits Neutralizing Antibodies and CD4 T Cell Responses after a Single Immunization in Mice

T-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 26 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mounted at least one CD4 T-cell response, and 48% of individuals mounted detectable SARS-CoV-2-specific circulating T follicular helper cells (cTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific cTfh responses across all three protein specificities correlated with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, cTfh responses, particularly to the M protein, increased in convalescence, and robust cTfh responses with magnitudes greater than 5% were detected at the second convalescent visit, a median of 38 days post-symptom onset. CD4 T-cell responses declined but persisted at low magnitudes three months and six months after symptom onset. These data deepen our understanding of antigen-specific cTfh responses in SARS-CoV-2 infection, suggesting that in addition to S protein, M and N protein-specific cTfh may also assist in the development of neutralizing antibodies and that cTfh response formation may be delayed in SARS-CoV-2 infection.

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Pre-existing Immunity to Japanese Encephalitis Virus Alters CD4 T Cell Responses to Zika Virus Inactivated Vaccine

Frontiers in Immunology ◽

10.3389/fimmu.2021.640190 ◽

2021 ◽

Vol 12 ◽

Author(s):

Noemia S. Lima ◽

Damee Moon ◽

Samuel Darko ◽

Rafael A. De La Barrera ◽

Leyi Lin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Japanese Encephalitis Virus ◽

Japanese Encephalitis ◽

Zika Virus ◽

Cd4 T Cells ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

The epidemic spread of Zika virus (ZIKV), associated with devastating neurologic syndromes, has driven the development of multiple ZIKV vaccines candidates. An effective vaccine should induce ZIKV-specific T cell responses, which are shown to improve the establishment of humoral immunity and contribute to viral clearance. Here we investigated how previous immunization against Japanese encephalitis virus (JEV) and yellow fever virus (YFV) influences T cell responses elicited by a Zika purified-inactivated virus (ZPIV) vaccine. We demonstrate that three doses of ZPIV vaccine elicited robust CD4 T cell responses to ZIKV structural proteins, while ZIKV-specific CD4 T cells in pre-immunized individuals with JEV vaccine, but not YFV vaccine, were more durable and directed predominantly toward conserved epitopes, which elicited Th1 and Th2 cytokine production. In addition, T cell receptor repertoire analysis revealed preferential expansion of cross-reactive clonotypes between JEV and ZIKV, suggesting that pre-existing immunity against JEV may prime the establishment of stronger CD4 T cell responses to ZPIV vaccination. These CD4 T cell responses correlated with titers of ZIKV-neutralizing antibodies in the JEV pre-vaccinated group, but not in flavivirus-naïve or YFV pre-vaccinated individuals, suggesting a stronger contribution of CD4 T cells in the generation of neutralizing antibodies in the context of JEV-ZIKV cross-reactivity.

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Impairment of Cd4+ T Cell Responses during Chronic Virus Infection Prevents Neutralizing Antibody Responses against Virus Escape Mutants

Journal of Experimental Medicine ◽

10.1084/jem.193.3.297 ◽

2001 ◽

Vol 193 (3) ◽

pp. 297-306 ◽

Cited By ~ 68

Author(s):

Adrian Ciurea ◽

Lukas Hunziker ◽

Paul Klenerman ◽

Hans Hengartner ◽

Rolf M. Zinkernagel

Keyword(s):

T Cell ◽

Virus Infection ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Surface Glycoprotein ◽

Cd4 T Cell ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Virus Escape ◽

Escape Mutants

We have shown previously that neutralizing antibodies (nAbs) are important contributors to the long-term immune control of lymphocytic choriomeningitis virus infection, particularly if cytotoxic T cell responses are low or absent. Nevertheless, virus escape from the nAb response due to mutations within the surface glycoprotein gene may subsequently allow the virus to persist. Here we show that most of the antibody-escape viral mutants retain their immunogenicity. We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4+ T cell responsiveness during the establishment of viral persistence. Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

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An adjuvanted subunit SARS-CoV-2 spike protein vaccine provides protection against Covid-19 infection and transmission

10.21203/rs.3.rs-902649/v1 ◽

2021 ◽

Author(s):

Kairat Tabynov ◽

Nurkeldi Turebekov ◽

Meruert Babayeva ◽

Gleb Fomin ◽

Toktasyn Yerubaev ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Candidate ◽

T Cell Responses ◽

Spike Protein ◽

Effective Vaccine ◽

Protein Vaccine ◽

Wild Type ◽

Cell Responses ◽

Ongoing Development

Abstract Recombinant protein approaches offer major promise for safe and effective vaccine prevention of SARS-CoV-2 infection. We developed a recombinant spike protein vaccine (called NARUVAX-C19) and characterized its ability when formulated with a nanoemulsion adjuvant to induce anti-spike antibody and T-cell responses and provide protection including against viral transmission in rodent. In mice, NARUVAX-C19 vaccine administered intramuscularly twice at 21-day interval elicited balanced Th1/Th2 humoral and T-cell responses with high titers of neutralizing antibodies against wild-type (D614G) and delta (B.1.617.2) variants. In Syrian hamsters, NARUVAX-C19 provided complete protection against wild-type (D614G) infection and prevented its transmission to naïve animals placed in the same cage as challenged animals. The results contrasted with only weak protection seen with a monomeric spike receptor binding domain (RBD) vaccine even when formulated with the same adjuvant. These encouraging results warrant ongoing development of this Covid-19 vaccine candidate.

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