Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

Huang, Ying; França, Monique; Allen, James D.; Shi, Hua; Ross, Ted M.

doi:10.3390/vaccines9070793

Cited by 34 publications

(44 citation statements)

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“…For the nasal cavity, ferret heads were removed and fixed in neutral buffered 10% formalin and subjected to decalcification in Kristensen’s solution. Tissues were subsequently processed, embedded in paraffin, sectioned at 5 μm, and stained with hematoxylin and eosin (H&E) as described before ( 62 ). Histopathological evaluation of lungs and nasal cavities was performed by a board-certified pathologist.…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets

Huang

Skarlupka

Jang

et al. 2022

J Virol

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are co-circulating in the human population. However, only a few cases of viral co-infection with these two viruses have been documented in humans with some people having severe disease and others mild disease. In order to examine this phenomenon, ferrets were co-infected with SARS-CoV-2 and human seasonal influenza A viruses (IAVs) (H1N1 or H3N2) and were compared to animals that received each virus alone. Ferrets were either immunologically naïve to both viruses or vaccinated with the 2019-2020 split-inactivated influenza virus vaccine. Co-infected naive ferrets lost significantly more body weight than ferrets infected with each virus alone and induced more severe inflammation in both the nose and lungs than ferrets single-infected with each virus. Co-infected naïve animals had predominantly higher IAV titers than SARS-CoV-2 titers, and IAVs efficiently transmitted to the co-housed ferrets by direct contact. Comparatively, SARS-CoV-2 failed to transmit to the ferrets that co-housed with co-infected ferrets by direct contact. Moreover, vaccination significantly reduced IAVs virus titers and shortened the viral shedding, but did not completely block influenza virus direct contact transmission. Notably, vaccination significantly ameliorated the influenza associated disease by protecting vaccinated animals from severe morbidity after IAV single infection or IAV and SARS-CoV-2 co-infection, suggesting that seasonal influenza virus vaccination is pivotal to prevent severe disease induced by IAVs and SARS-CoV-2 co-infection during the COVID-19 pandemic. Importance Influenza A viruses cause severe morbidity and mortality during each influenza virus season. The emergence of SARS-CoV-2 infection in the human population offers the opportunity to potential co-infections of both viruses. The development of useful animal models to asses pathogenesis, transmission, and viral evolution of these viruses as the co-infect a host is of critical importance for the development of vaccines and therapeutics. The ability to prevent the most severe effects of viral co-infections can be studied using effect co-infection ferret models described in this report.

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Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets

Huang

Skarlupka

Jang

et al. 2022

J Virol

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“…Porcine intestinal tissue was purchased from Lampire Biological Products (Pipersville, PA). The recombinant COBRA HA protein (designed for the H1N1 influenza subtype) was produced by Ted Ross’ laboratory at the University of Georgia …”

Section: Methodsmentioning

confidence: 99%

“…The recombinant COBRA HA protein (designed for the H1N1 influenza subtype) was produced by Ted Ross' laboratory at the University of Georgia. 21 PEI-Ox-DEX Gel Fabrication. Dextran (71 kDa) was modified with aldehyde groups via periodate oxidation to form oxidized dextran (Ox-DEX).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Development of an Intranasal Gel for the Delivery of a Broadly Acting Subunit Influenza Vaccine

Varma

Batty

Stiepel

et al. 2022

ACS Biomater. Sci. Eng.

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Influenza virus is a major cause of death on a global scale. Seasonal vaccines have been developed to combat influenza; however, they are not always highly effective. One strategy to develop a more broadly active influenza vaccine is the use of multiple rounds of layered consensus buildings to generate recombinant antigens, termed computationally optimized broadly reactive antigen (COBRA). Immunization with the COBRA hemagglutinin (HA) can elicit broad protection against multiple strains of a single influenza subtype (e.g., H1N1). We formulated a COBRA H1 HA with a stimulator of interferon genes agonist cyclic guanosine monophosphate−adenosine monophosphate (cGAMP) into a nasal gel for vaccination against influenza. The gel formulation was designed to increase mucoadhesion and nasal retention of the antigen and adjuvant to promote a strong mucosal response. It consisted of a Schiff base-crosslinked hydrogel between branched polyethyleneimine and oxidized dextran. Following a prime-boost-boost schedule, an intranasal gel containing cGAMP and model antigen ovalbumin (OVA) led to the faster generation of serum IgG, IgG1, and IgG2c and significantly greater serum IgG1 levels on day 42 compared to soluble controls. Additionally, OVA-specific IgA was detected in nasal, vaginal, and fecal samples for all groups, except the vehicle control. When the COBRA HA was given intranasally in a prime-boost schedule, the mice receiving the gel containing the COBRA and cGAMP had significantly higher serum IgG and IgG2c at day 41 compared to all groups, and only this group had IgA levels above the background in vaginal, nasal, and fecal samples. Overall, this study indicates the utility of an intranasal gel for the delivery of COBRAs for the generation of serum and mucosal humoral responses.

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“…Reneer et al, constructed an H2 COBRA HA vaccine and tested it in ferrets immunized against H2N3 attack, resulting in vaccinated ferrets exhibiting higher antibody titers and recognizing the highest number of H2 influenza viruses in a classical neutralization assay compared to wild-type H2 HA recombinant proteins [ 50 ]; Huang et al, used the COBRA approach to generate two new candidate COBRA HA vaccines, Y2 and Y4, from H1N1 isolates prevalent during 2013–2019. Mice vaccinated with Y2 and Y4 effectively reduced morbidity and mortality after infection with H1N1 influenza viruses, and vaccine-initiated antibodies associated with H1N1 isolates from 2009 to 2021 and pdm09-like viruses produced a high degree of cross-reactivity, with the strongest intensity of cross-reactivity in 2019–2021 [ 51 ]; Allen et al, first infected ferrets with three historical H3N2 species and then tested for expanded immune breadth with constructed COBRA or wild-type (WT) H3 VLP vaccine antigens and showed that, compared to the WT group, the COBRA group in all three historical H3N2 strains produced more cross-reactive antibodies and induced antibodies capable of neutralizing live virus infections of modern drifting H3N2 strains at higher titers [ 52 ].…”

Section: Development Of Universal Influenza Vaccinementioning

confidence: 99%

Influenza and Universal Vaccine Research in China

Zhang

et al. 2022

Viruses

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Influenza viruses usually cause seasonal influenza epidemics and influenza pandemics, resulting in acute respiratory illness and, in severe cases, multiple organ complications and even death, posing a serious global and human health burden. Compared with other countries, China has a large population base and a large number of influenza cases and deaths. Currently, influenza vaccination remains the most cost-effective and efficient way to prevent and control influenza, which can significantly reduce the risk of influenza virus infection and serious complications. The antigenicity of the influenza vaccine exhibits good protective efficacy when matched to the seasonal epidemic strain. However, when influenza viruses undergo rapid and sustained antigenic drift resulting in a mismatch between the vaccine strain and the epidemic strain, the protective effect is greatly reduced. As a result, the flu vaccine must be reformulated and readministered annually, causing a significant drain on human and financial resources. Therefore, the development of a universal influenza vaccine is necessary for the complete fight against the influenza virus. By statistically analyzing cases related to influenza virus infection and death in China in recent years, this paper describes the existing marketed vaccines, vaccine distribution and vaccination in China and summarizes the candidate immunogens designed based on the structure of influenza virus, hoping to provide ideas for the design and development of new influenza vaccines in the future.

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Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

Cited by 34 publications

References 50 publications

SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets

SARS-CoV-2 and Influenza A Virus Coinfections in Ferrets

Development of an Intranasal Gel for the Delivery of a Broadly Acting Subunit Influenza Vaccine

Influenza and Universal Vaccine Research in China

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