Infection with Seasonal Influenza Virus Elicits CD4 T Cells Specific for Genetically Conserved Epitopes That Can Be Rapidly Mobilized for Protective Immunity to Pandemic H1N1 Influenza Virus

Self Cite

Influenza virus vaccination strategies are focused upon the elicitation of protective antibody responses through administration of viral protein through either inactivated virions or live attenuated virus. Often overlooked in this strategy is the CD4 T cell response: how it develops into memory, and how it may support future primary B cell responses to heterologous infection. Through the utilization of a peptide-priming regimen, this study describes a strategy for developing CD4 T cell memory with the capacity to robustly expand in the lung-draining lymph node after live influenza virus infection. Not only were frequencies of antigen-specific CD4 T cells enhanced, but these cells also supported an accelerated primary B cell response to influenza virusderived protein, evidenced by high anti-nucleoprotein (NP) serum antibody titers early, while there is still active viral replication ongoing in the lung. NP-specific antibody-secreting cells and heightened frequencies of germinal center B cells and follicular T helper cells were also readily detectable in the draining lymph node. Surprisingly, a boosted memory CD4 T cell response was not sufficient to provide intermolecular help for antibody responses. Our study demonstrates that CD4 T cell help is selective and limiting to the primary antibody response to influenza virus infection and that preemptive priming of CD4 T cell help can promote effective and rapid conversion of naive B cells to mature antibody-secreting cells.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CD4 T Cell Help Is Limiting and Selective during the Primary B Cell Response to Influenza Virus Infection

Alam

Knowlden

Sangster

et al. 2014

Self Cite

“…However, the constantly evolving nature of seasonal influenza viruses (antigenic drift) requires yearly review of vaccine strains and the sudden emergence of substantially different strains (antigenic shift) can lead to a pandemic. It was demonstrated in humans and in animal models that natural influenza virus infection confers protection against homologous and heterologous virus strains through CD4 and CD8 T cells mediated immunity (1)(2)(3)(4)(5). On the contrary, protective immunity induced by most inactivated influenza vaccines (IIV) has been correlated with antibodies directed to virion-expressed hemagglutinin (HA) (6)(7)(8).…”

mentioning

confidence: 99%

Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

Brazzoli

Magini

Bonci

et al. 2016

137

130

Seasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. The impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. In this study, we used the SAM technology and characterized the immunogenicity and efficacy of a self-amplifying mRNA expressing influenza virus hemagglutinin ( IMPORTANCEIn this study, we describe protective immune responses in mice and ferrets after vaccination with a novel HA-based influenza vaccine. This novel type of vaccine elicits both humoral and cellular immune responses. Although vaccine-specific antibodies are the key players in mediating protection from homologous influenza virus infections, vaccine-specific T cells contribute to the control of heterologous infections. The rapid production capacity and the synthetic origin of the vaccine antigen make the SAM platform particularly exploitable in case of influenza pandemic.

“…In light of the recent influenza pandemic, HSI may be a contributing factor to its mildness and lower mortality rates compared to previous pandemics. Aside from the detection of preexisting antibodies to HA in older individuals (38), there was also preexisting T cell immunity to the pandemic strain, as exemplified by the presence of both CD8 ϩ and CD4 ϩ T cell epitopes generated from previous encounters with seasonal influenza virus strains (1,18,28,59,82). Thus, HSI significantly impacted the course of the recent influenza pandemic.…”

Section: We Established a Human Cd4mentioning

confidence: 99%

A Human CD4⁺T Cell Epitope in the Influenza Hemagglutinin Is Cross-Reactive to Influenza A Virus Subtypes and to Influenza B Virus

Babon

Cruz

Ennis

et al. 2012

The hemagglutinin protein (HA) of the influenza virus family is a major antigen for protective immunity. Thus, it is a relevant target for developing vaccines. Here, we describe a human CD4 + T cell epitope in the influenza virus HA that lies in the fusion peptide of the HA. This epitope is well conserved in all 16 subtypes of the HA protein of influenza A virus and the HA protein of influenza B virus. By stimulating peripheral blood mononuclear cells (PBMCs) from a healthy adult donor with peptides covering the entire HA protein based on the sequence of A/Japan/305/1957 (H2N2), we generated a T cell line specific to this epitope. This CD4 + T cell line recognizes target cells infected with influenza A virus seasonal H1N1 and H3N2 strains, a reassortant H2N1 strain, the 2009 pandemic H1N1 strain, and influenza B virus in cytotoxicity assays and intracellular-cytokine-staining assays. It also lysed target cells infected with avian H5N1 virus. We screened healthy adult PBMCs for T cell responses specific to this epitope and found individuals who had ex vivo gamma interferon (IFN-γ) responses to the peptide epitope in enzyme-linked immunospot (ELISPOT) assays. Almost all donors who responded to the epitope had the HLA-DRB1*09 allele, a relatively common HLA allele. Although natural infection or standard vaccination may not induce strong T and B cell responses to this highly conserved epitope in the fusion peptide, it may be possible to develop a vaccination strategy to induce these CD4 + T cells, which are cross-reactive to both influenza A and B viruses.