Computationally Optimized Broadly Reactive H2 HA Influenza Vaccines Elicited Broadly Cross-Reactive Antibodies and Protected Mice from Viral Challenges

Abstract

Influenza viruses have caused numerous pandemics throughout human history. The 1957 influenza pandemic was initiated by an H2N2 influenza virus. This H2N2 influenza virus was the result of a reassortment event between a circulating H2N2 avian virus and the seasonal H1N1 viruses in humans. Previously, our group has demonstrated the effectiveness of HA antigens derived using computationally optimized broadly reactive antigen (COBRA) methodology against H1N1, H3N2, and H5N1 viruses. Using the COBRA methodology, H2 HA COBRA antigens were designed using sequences from H2N2 viruses isolated from humans in the 1950s and 1960s, as well as, H2Nx viruses isolated from avian and mammalian species between the 1950s and 2016. In this manuscript, the effectiveness of H2 COBRA HA antigens (Z1, Z3, Z5, and Z7) were evaluated in DBA/2J mice and compared to wild-type H2 HA antigens. The COBRA HA vaccines elicited neutralizing antibodies to the majority of viruses in our H2 HA panel and across all three clades as measured by HAI and neutralization assays. Comparatively, several wild-type HA vaccines elicited antibodies against a majority of the viruses in the H2 HA panel. DBA/2J mice vaccinated with COBRA vaccines showed increase survival for all three viral challenges as compared to the wild-type H2 vaccines. In particular, the Z1 COBRA is a promising candidate for future work towards a pandemic H2 influenza vaccine. IMPORTANCE H2N2 influenza has caused at least one pandemic in the past. Given that individuals born after 1968 have not been exposed to H2N2 influenza viruses, a future pandemic caused by H2 influenza is likely. An effective H2 influenza vaccine would need to elicit broadly cross-reactive antibodies to multiple H2 influenza viruses. Choosing a wild-type virus to create a vaccine may elicit a narrow immune response and not protect against multiple H2 influenza viruses. COBRA H2 HA vaccines were developed and evaluated in mice along with wild-type H2 HA vaccines. Multiple COBRA H2 HA vaccines protected mice from all three viral challenges and produced broadly cross-reactive neutralizing antibodies to H2 influenza viruses.

Strategies Targeting Hemagglutinin as a Universal Influenza Vaccine

“…The COBRA strategy achieves this through multiple rounds of consensus generation. A COBRA vaccine strategy has been developed and tested for H1 [81][82][83][84][85], H2 [86], H3 [87,88], H5 [89][90][91][92][93][94][95][96], and swine H1 [97]. These COBRA immunogens have primarily been expressed using a VLP platform but have also been explored using ferritin nanoparticles [84] and recombinant live influenza virus [83].…”

Targeting Antigens for Universal Influenza Vaccine Development

“…This vaccine candidate showed an increase in HI activity compared to wild-type HA vaccine. COBRA H2 HA antigens were also developed using human and avian H2 HA sequences, and the use of this vaccine generated broadly cross-reactive Abs against both historical human H2N2, avian, and mammalian H2 viruses recently isolated in mice [63]. Mosaic HA vaccination approach.…”

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

“…In order to overcome antigenic drift and shift, and improve influenza vaccine efficacy, our group has developed a methodology, termed computationally optimized broadly reactive antigens (COBRA) to design HA immunogens for different subtypes of IAVs, including H1, H2, H3, and H5 [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. This COBRA methodology employs multiple rounds of layered consensus building to generate influenza virus vaccine HA antigens that are capable of eliciting broadly reactive HA-specific antibodies that protect against both seasonal and pandemic influenza virus strains [ 15 , 16 , 17 , 20 ].…”