Influenza H5 Hemagglutinin DNA Primes the Antibody Response Elicited by the Live Attenuated Influenza A/Vietnam/1203/2004 Vaccine in Ferrets

Suguitan, Amorsolo L.; Cheng, Xing; Wang, Weijia; Wang, Shixia; Jin, Hong; Lu, Shan

doi:10.1371/journal.pone.0021942

Cited by 36 publications

(31 citation statements)

References 49 publications

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“…Subsequent infection or immunization with a variant strain would likely be an effective route to generate broadly reactive anti-H5 antibodies. Such strategies are known to be effective within influenza subtypes (25,48,49). Our structural understanding of H5.3 supports the hypothesis that repeated challenge through immunization or infection is an effective strategy to enhance universal binding determinants, such as a CDRH3 loop that effectively binds conserved features of the RBS, similar to the natural receptor, while minimizing strainspecific interactions.…”

Section: Resultssupporting

confidence: 67%

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Winarski

Thornburg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. Here, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility. structural biology | immunity | antigen recognition | affinity maturation | influenza I nfluenza remains a major public health concern because seasonal influenza infects 600 million to 1.1 billion people annually, resulting in 3-5 million cases of severe disease, and 250,000-500,000 deaths (1). By comparison, the four influenza pandemics of the 20th century, caused by novel influenza strains infecting the immunologically naive human population, resulted in 50-100 million deaths (1-4). Influenza A immunity is principally mediated by the antibody response to the viral glycoprotein, hemagglutinin (HA) (5). HA is expressed as a preprotein, HA0, assembled as a trimer on the viral envelope, and cleaved by host proteases into HA1 and HA2. HA1 is a largely globular domain responsible for receptor binding, and HA2 is a rod-shaped helical bundle responsible for membrane fusion (Fig. 1A) (5). There are 18 genetically distinct subtypes of influenza A HA (H1-H18), of which only H1 and H3 currently circulate among humans (1,(6)(7)(8)(9).Despite the widespread presence of H5N1 influenza viruses in wild birds, the virus is not currently transmissible within the human population. Human-to-human transmission is inefficient and is partially restricted by the receptor specificity of the virus; human-type HAs preferentially recognize α2,6-linked sialic acid whereas avian-type HAs prefer α2,3-linked sialic acid (1, 10-12). However, there have been >600 human cases of H5N1 infection since 2004, resulting from the direct transmission of the virus from birds to humans, associated with an ∼60% mortality rate. There is the potential for a significant pandemic if H5 viruses develop the ability to spread efficiently b...

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Section: Resultssupporting

confidence: 67%

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Winarski

Thornburg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…With the current controversy surrounding the use of ferrets in influenza studies, it is important to remember that the reason for using ferrets extends far beyond that of providing a model for H5N1 transmission, as many investigators have shown ferrets to be a superlative platform for testing and developing influenza therapeutics including the investigation of influenza vaccines [26][27][28][29][30]. Importantly, when infected with respiratory viruses, ferrets display many of the symptoms and pathological features seen in infected humans [31][32][33] .…”

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confidence: 99%

The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development

Banner

Kelvin²

2012

J Infect Dev Ctries

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Highly pathogenic avian influenza H5N1 is a threat to global public health as a natural pandemic causing agent but has recently been considered a bioterrorism concern. The evolving view of the H5N1 virus necessitates the re-evaluation of the current status of H5N1 therapeutics and prophylactics, in particular the preparation of viable H5N1 vaccination strategies as well as the use of ferrets in influenza research. Here the highly pathogenic H5N1 virus dilemma is discussed in context with the current H5N1 vaccine status and the use of the ferret model. Previously, the development of various H5N1 vaccine platforms have been attempted, many of them tested in the ferret model, including vector vaccines, adjuvant vaccines, DNA vaccines, and reverse engineered vaccines. Moreover, as ferrets are a superlative animal model for influenza investigation and vaccine testing, it is imperative that this model is recognized for its uses in prophylactic development and not only as an agent for creating transmissible influenza viruses. Elucidating the ferret immune response and creating ferret immune reagents remain important goals in conjunction with the development and manufacture of H5N1 vaccines. In summary, an efficacious H5N1 vaccine is urgently needed and the ferret model remains an appropriate model for its development.J Infect Dev Ctries 2012; 6(6):465-469.

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“…The absence of anti-HA antibodies in such DNA-vaccinated groups was not surprising because previous dose-response studies have demonstrated variability in induction of HI antibodies, which play a major role in protection against avian influenza (Jiang et al, 2007). Moreover, poor humoral response has been previously reported with a homologous DNA-DNA prime-boost vaccination strategy (Suguitan et al, 2011). It is worth noting that in the present study, the absence of HI titers was directly related to the lowering of protective efficacy, in contrast to previous studies that showed protection in chickens despite the lack of any detectable anti-HA antibody titer (Kodihalli et al, 1997;Jiang et al, 2007).…”

Section: Discussionmentioning

confidence: 91%

“…Enhancement could be attributed to the induction of cell-mediated immune response as DNA vaccines are potent mobilizers of cellular immune response (Donnelly et al, 1997;Khan, 2013) via direct transfection of antigen presenting cells and/or cross priming (Iurescia et al, 2014). Earlier studies have shown that priming with HA-DNA is as effective as immunization with live attenuated influenza vaccine (LAIV) or with inactivated adjuvanted influenza vaccine (Suguitan et al, 2011). Results of the present study demonstrate that a prime-boost regimen using pcDNA3.1D/HA1 purified recombinant plasmid with the inactivated H5N2 vaccine is more immunogenic than the use of either pcDNA3.1D/HA1 purified recombinant plasmid or inactivated H5N2 vaccine alone.…”

Section: Discussionmentioning

confidence: 99%

Protective efficacy of a prime-boost protocol using H5-DNA plasmid as prime and inactivated H5N2 vaccine as the booster against the Egyptian avian influenza challenge virus

Hussein¹,

Ahmed²,

Aly³

et al. 2016

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Summary. -In this study, a recombinant DNA plasmid was constructed, encoding for HA1 of a selected Egyptian H5N1 virus (isolated during the 2012 outbreaks). In the immunization and challenge experiments, SPF chickens received 1 or 2 doses of H5-DNA plasmid prime, and boosted with the inactivated H5N2 vaccine. Haemagglutination inhibition (HI) titers, protection levels, and the magnitude of virus shedding were compared to that of the chickens that received either DNA plasmid or inactivated H5N2 vaccine alone. H5N1 virus A/chicken/Egypt/128s/2012 (H5N1) highly pathogenic avian influenza (HPAI) clade 2.2.1/C was used for the challenge. Chickens immunized with 1 or 2 doses of H5-DNA vaccine failed to overcome the challenge with 0% and 10% protection, respectively. Quantitative real-time reverse transcription-PCR revealed virus shedding of 2.2 x 10 4 PCR copies/ml 3 days post challenge (dpc) in the only surviving bird from the group that received 2 doses of plasmid. However, chickens immunized with 1 or 2 doses of H5-DNA plasmid as prime and inactivated H5N2 vaccine as booster, showed 80% protection after challenge, with a viral shedding of 1.2 x 10 4 PCR copies/ml (1 dose) and 1.6 x 10 4 PCR copies/ml (2 doses) 3 dpc. The surviving birds in both groups did not shed the virus at 5 and 7 dpc. In H5N2-vaccinated chickens, protection levels were 70% with relatively high virus shedding (1.8 x 10 4 PCR copies/ml) 3 dpc. HI titers were protective to the surviving chickens. This study reports the efficacy of H5-DNA plasmid to augment reduction in viral shedding and to provide better protection when applied in a prime-boost program with the inactivated AI vaccine.Keywords: avian H5N1 influenza; inactivated H5N2 vaccine; DNA plasmid; hemagglutinin; prime-boost Email: husvirol@cu.edu.eg; phone: +201002159364. Abbreviations: AI(V) = avian influenza (virus); dpc = days post challenge; EID 50 = egg infective dose (50%); HA1 = hemagglutinin one (the part representing influenza hemagglutinin globular head); HI = hemagglutination inhibition; HPAI = highly pathogenic avian influenza; qRT-PCR = quantitative real-time reverse transcriptionpolymerase chain reaction; SPF = specific pathogen free

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Influenza H5 Hemagglutinin DNA Primes the Antibody Response Elicited by the Live Attenuated Influenza A/Vietnam/1203/2004 Vaccine in Ferrets

Cited by 36 publications

References 49 publications

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development

Protective efficacy of a prime-boost protocol using H5-DNA plasmid as prime and inactivated H5N2 vaccine as the booster against the Egyptian avian influenza challenge virus

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