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Prophylactic Protection Against Respiratory Viruses Conferred by a Prototype Live Attenuated Influenza Virus Vaccine.

ABSTRACT: The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

SUBMITTER: Rathnasinghe R

PROVIDER: S-EPMC8366806 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recurring epizootic influenza A virus (IAV) infections in domestic livestock such as swine and poultry are associated with a substantial economic burden and pose a constant threat to human health. Therefore, universally applicable and safe animal vaccines are urgently needed. We recently demonstrated that a reassortment-incompatible chimeric bat H17N10 virus harboring the A/swan/Germany/R65/2006 (H5N1) surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) can be efficiently used as a modified live influenza vaccine (MLIV). To ensure vaccine safety and, thus, improve the applicability of this novel MLIV for mammalian usage, we performed consecutive passaging in eggs and chickens. Following passaging, we identified mutations in the viral polymerase subunits PB2 (I382S), PB1 (Q694H and I695K), and PA (E141K). Strikingly, recombinant chimeric viruses encoding these mutations showed no growth deficiencies in avian cells but displayed impaired growth in human cells and mice. Homologous prime-boost immunization of mice with one of these avian-adapted chimeric viruses, designated rR65mono/H17N10EP18, elicited a strong neutralizing antibody response and conferred full protection against lethal highly pathogenic avian influenza virus (HPAIV) H5N1 challenge infection. Importantly, the insertion of the avian-adaptive mutations into the conventional avian-like A/SC35M/1980 (H7N7) and prototypic human A/PR/8/34 (H1N1) viruses led to attenuated viral growth in human cells and mice. Collectively, our data show that the polymerase mutations identified here can be utilized to further improve the safety of our novel H17N10-based MLIV candidates for future mammalian applications. IMPORTANCE Recurring influenza A virus outbreaks in livestock, particularly in swine and chickens, pose a constant threat to humans. Live attenuated influenza vaccines (LAIVs) might be a potent tool to prevent epizootic outbreaks and the resulting human IAV infections; however, LAIVs have several disadvantages, especially in terms of reassortment with circulating IAVs. Notably, the newly identified bat influenza A viruses H17N10 and H18N11 cannot reassort with conventional IAVs. Chimeric bat influenza A viruses encoding surface glycoproteins of conventional IAV subtypes might thus function as safe and applicable modified live influenza vaccines (MLIVs).

Project description:There are no approved vaccines against the life-threatening Middle East respiratory syndrome coronavirus (MERS-CoV). Attenuated vaccines have proven their potential to induce strong and long-lasting immune responses. We have previously described that severe acute respiratory syndrome coronavirus (SARS-CoV) envelope (E) protein is a virulence factor. Based on this knowledge, a collection of mutants carrying partial deletions spanning the C-terminal domain of the E protein (rMERS-CoV-E*) has been generated using a reverse genetics system. One of these mutants, MERS-CoV-E*Δ2in, was attenuated and provided full protection in a challenge with virulent MERS-CoV after a single immunization dose. The MERS-CoV-E*Δ2in mutant was stable as it maintained its attenuation after 16 passages in cell cultures and has been selected as a promising vaccine candidate.IMPORTANCE The emergence of the new highly pathogenic human coronavirus SARS-CoV-2 that has already infected more than 80 million persons, killing nearly two million of them, clearly indicates the need to design efficient and safe vaccines protecting from these coronaviruses. Modern vaccines can be derived from virus-host interaction research directed to the identification of signaling pathways essential for virus replication and for virus-induced pathogenesis, in order to learn how to attenuate these viruses and design vaccines. Using a reverse genetics system developed in our laboratory, an infectious cDNA clone of MERS-CoV was engineered. Using this cDNA, we sequentially deleted several predicted and conserved motifs within the envelope (E) protein of MERS-CoV, previously associated with the presence of virulence factors. The in vitro and in vivo evaluation of these deletion mutants highlighted the relevance of predicted linear motifs in viral pathogenesis. Two of them, an Atg8 protein binding motif (Atg8-BM), and a forkhead-associated binding motif (FHA-BM), when deleted, rendered an attenuated virus that was evaluated as a vaccine candidate, leading to full protection against challenge with a lethal dose of MERS-CoV. This approach can be extended to the engineering of vaccines protecting against the new pandemic SARS-CoV-2.

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Prophylactic Protection Against Respiratory Viruses Conferred by a Prototype Live Attenuated Influenza Virus Vaccine.

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