Development of Clade-Specific and Broadly Reactive Live Attenuated Influenza Virus Vaccines against Rapidly Evolving H5 Subtype Viruses

Boonnak, Kobporn; Matsuoka, Yumiko; Wang, Weijia; Suguitan, Amorsolo L.; Chen, Zhongying; Paskel, Myeisha; Baz, Mariana; Moore, Ian N.; Jin, Hong; Subbarao, Kanta

doi:10.1128/jvi.00547-17

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…Collectively, our findings suggest that many H10 viruses replicate in mammals without prior adaptation. Importantly, we previously evaluated a range of other avian influenza viruses, including H2, H5, and H6 subtypes, and found that many avian influenza viruses can also replicate in mice and ferrets (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Biological Properties and Cross-Reactive Antibody Response to H10 Influenza Viruses in Ferrets

Sutton

Lamirande

Czakó

et al. 2017

J Virol

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The recent outbreak of avian origin H10N7 influenza among seals in Northern Europe, and two fatal human infections with an avian H10N8 virus in China, have demonstrated that H10 viruses can spread between mammals and cause severe disease in humans. To gain insight into the potential for H10 viruses to cross the species barrier and identify a candidate vaccine strain, we evaluated the in vitro and in vivo properties and antibody response in ferrets to 20 diverse H10 viruses. H10 virus infection of ferrets caused variable weight loss and all 20 viruses replicated throughout the respiratory tract; however, replication in the lungs was highly variable. In glycan-binding assays, the H10 viruses preferentially bound "avian-like" α2,3-linked sialic acids. Importantly, several isolates also displayed strong binding to long-chain "human-like" α2,6-linked sialic acids, and exhibited comparable or elevated neuraminidase activity relative to human H1N1, H2N2, and H3N2 viruses. In hemagglutination inhibition assays, 12 antisera cross-reacted with ≥ 14 of 20 H10 viruses, and 7 viruses induced neutralizing activity against ≥ 15 of the 20 viruses. By combining data on weight loss, viral replication, and the cross-reactive antibody response, we identified A/mallard/Portugal/79906/2009 (H10N7) as a suitable virus for vaccine development. Collectively, our findings suggest that H10 viruses may continue to sporadically infect humans and other mammals, underscoring the importance of developing an H10 vaccine for pandemic preparedness. Avian origin H10 influenza viruses sporadically infect humans and other mammals; however, little is known about viruses of this subtype. Thus, we characterized the biological properties of 20 H10 viruses in vitro and in ferrets. Infection caused mild to moderate weight loss (5-15%), with robust viral replication in the nasal tissues and variable replication in the lung. H10 viruses preferentially bind "avian-like" sialic acids, although several isolates also displayed binding to "human-like" sialic acid receptors. This is consistent with the ability of H10 viruses to cross the species barrier, and warrants selection of an H10 vaccine strain. By evaluating the cross-reactive antibody response to the H10 viruses, and combining this analysis with viral replication and weight loss findings, we identified A/mallard/Portugal/79906/2009 (H10N7) as a suitable H10 vaccine strain.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Biological Properties and Cross-Reactive Antibody Response to H10 Influenza Viruses in Ferrets

Sutton

Lamirande

Czakó

et al. 2017

J Virol

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“…Even in the 25 combinations with lower levels of survival, the MDT was prolonged for most vaccinated groups compared to the sham groups (Table S1), suggesting partial but inadequate protection to prevent death. For example, vaccine 2 probably explaining why some vaccines were able to recognize this clade before this period (19).…”

Section: Downloaded Frommentioning

confidence: 99%

Cross-Protection by Inactivated H5 Prepandemic Vaccine Seed Strains against Diverse Goose/Guangdong Lineage H5N1 Highly Pathogenic Avian Influenza Viruses

Criado

Silva

Lee

et al. 2020

J Virol

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The highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 lineage (Gs/GD) is endemic in poultry across several countries in the world, and has caused lethal, sporadic infections in humans. Vaccines are important in HPAI control for both poultry and in pre-pandemic preparedness in humans. This study assessed inactivated pre-pandemic vaccine strains in a One Health framework, focusing on the genetic and antigenic diversity of field H5N1 Gs/GD viruses from the agricultural sector and assessing cross protection in a chicken challenge model. Nearly half (47.92%) of the forty-eight combinations of vaccine/challenge viruses examined had bird protection of 80% or above. Most vaccinated groups had prolonged mean death time (MDT) and the virus shedding titers were significantly lower compared to the sham group (p≤ 0.05). The antibody titers in the pre-challenge sera were not predictive of protection. Although vaccinated birds had higher titers of hemagglutination inhibiting (HI) antibodies against homologous vaccine antigen, most of them also had lower or no antibody titer against the challenge antigen. The comparison of all parameters, homologous or closely related vaccine and challenge viruses, gave the best prediction protection. Through additional analysis, we identified a pattern of epitopes substitutions in the hemagglutinin (HA) of each challenge virus that impacted protection, regardless of the vaccine used. These changes were situated in the antigenic sites and/or reported epitopes associated with virus escape from antibody neutralization. As a result, this study highlights virus diversity, immune response complexity, and the importance of strain selection for vaccine development to control H5N1 HPAIV in the agricultural sector and for human pre-pandemic preparedness. We suggest that the engineering of specific antigenic sites can improve the immunogenicity of H5 vaccines. Importance The sustained circulation of highly pathogenic avian influenza virus (HPAIV) H5N1 A/goose/Guangdong/1996 lineage (Gs/GD) in the agricultural sector and some wild birds has led to the evolution and selection of distinct viral lineages involved in the escape from vaccine protection. Our results using inactivated vaccine candidates from the human pandemic preparedness program in a chicken challenge model identified critical antigenic conformational epitopes on the H5 hemagglutinin (HA) from different clades that were associated with antibody recognition and escape. Even though other investigators have reported epitope mapping in the H5 HA, much of this information pertains to epitopes reactive towards mouse antibodies. Our findings validate changes in antigenic epitopes of HA associated with virus escape from antibody neutralization in chickens, which has direct relevance to field protection and virus evolution. Therefore, the knowledge of these immunodominant regions is essential to proactively develop diagnostic tests, improve surveillance platforms to monitor AIV outbreaks, and design more efficient and broad-spectrum agricultural and human prepandemic vaccines.

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“…Our approach to selecting viruses to target for pLAIV development was to 1) select a subtype of interest, 2) generate postinfection ferret antisera against 10-14 temporally and geographically distinct viruses from different genetic clades, and 3) test the antisera against the viruses in a checkerboard fashion to identify the virus(es) that induced the highest titer Ab that also cross-reacted most broadly against the other viruses. We used this approach to select H2, H6, H5, and H7 viruses for pLAIV development (100)(101)(102)(103) and evaluated their breadth of immunogenicity and efficacy in mice and/or ferrets that were challenged with homologous and heterologous IAVs (102). Two other approaches designed to generate a more broadly cross-reactive Avian influenza HA proteins delivered as standard inactivated influenza vaccines (such as pIIV) are poorly immunogenic, but this can be overcome with higher doses of Ag or the addition of adjuvants.…”

Section: Broadly Cross-protective and Universal Influenza Vaccinesmentioning

confidence: 99%

Immune Responses to Avian Influenza Viruses

Koutsakos

Kedzierska

Subbarao

2019

The Journal of Immunology

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Avian influenza A viruses (IAVs) naturally infect different avian species, and aquatic birds are their natural reservoir. Sporadically, avian IAVs can be transmitted to humans, and some, such as H5N1 and H7N9 viruses, cause severe disease in humans. Antigenically novel avian influenza viruses that infect and cause disease in humans pose a potential pandemic threat if they are able to spread efficiently from person to person. The immune response of the host is crucial in determining disease pathogenesis and is the basis for the development of control strategies. In this review, we examine the innate and adaptive immune responses to avian influenza viruses and their role in disease and recovery. Furthermore, we discuss the progress in developing vaccines against avian IAVs and summarize obstacles in designing universal and pandemic influenza vaccines.

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Development of Clade-Specific and Broadly Reactive Live Attenuated Influenza Virus Vaccines against Rapidly Evolving H5 Subtype Viruses

Cited by 9 publications

References 41 publications

Evaluation of the Biological Properties and Cross-Reactive Antibody Response to H10 Influenza Viruses in Ferrets

Evaluation of the Biological Properties and Cross-Reactive Antibody Response to H10 Influenza Viruses in Ferrets

Cross-Protection by Inactivated H5 Prepandemic Vaccine Seed Strains against Diverse Goose/Guangdong Lineage H5N1 Highly Pathogenic Avian Influenza Viruses

Immune Responses to Avian Influenza Viruses

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