Evaluation of Live Attenuated Influenza A Virus H6 Vaccines in Mice and Ferrets

Chen, Zhongying; Santos, Celia; Aspelund, Amy; Gillim-Ross, Laura; Jin, Hong; Kemble, George; Subbarao, Kanta

doi:10.1128/jvi.01775-08

Cited by 55 publications

(61 citation statements)

References 41 publications

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“…Thus, it is important to assess the immune response to influenza A (H1N1) vaccines in different animal models to establish appropriate models for the preclinical evaluation of vaccines. 28,29 The efficacy and protective effect of the influenza A (H1N1) split vaccine were not investigated in this study; thus, additional studies will be needed to determine the efficacy, immunogenicity, safety, toxicity and other pharmacological parameters of the influenza A (H1N1) vaccine using appropriate experimental animals before their protective effects in primates and humans can be tested.…”

Section: Discussionmentioning

confidence: 99%

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Response of BALB/c mice to a monovalent influenza A (H1N1) 2009 split vaccine

Yang

Tang

et al. 2010

Cell Mol Immunol

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The novel influenza A (H1N1) 2009 virus has emerged to cause the first pandemic of the twenty-first century. Disease outbreaks caused by the influenza A (H1N1) virus have prompted concerns about the potential for a pandemic and have driven the development of vaccines against this subtype of influenza A. In this study, we developed a monovalent influenza A (H1N1) split vaccine and evaluated its effects in BALB/c mice. Mice were immunized subcutaneously with 2 doses of the vaccine containing hemagglutinin (HA) alone or HA plus an aluminum hydroxide (Al(OH) 3 ) adjuvant. Immunization with varying doses of HA (3.75, 7.5,15,30, 45 or 60 mg) was performed to induce the production of neutralizing antibodies. The vaccine elicited strong hemagglutination inhibition (HI) and microneutralization, and addition of the adjuvant augmented the antibody response. A preliminary safety evaluation showed that the vaccine was not toxic at large doses (0.5 ml containing 60 mg HA1600 mg Al(OH) 3 or 60 mg HA). Moreover, the vaccine was found to be safe at a dose of 120 mg HA11200 mg Al(OH) 3 or 120 mg HA in 1.0 ml in rats. In conclusion, the present study provides support for the clinical evaluation of influenza A (H1N1) vaccination as a public health intervention to mitigate a possible pandemic. Additionally, our findings support the further evaluation of the vaccine used in this study in primates or humans.

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Section: Discussionmentioning

confidence: 99%

“…Adjuvants are therefore required to elicit protective immune responses at antigen doses equal to or lower than those used in current seasonal influenza vaccines. [5][6][7] Aluminum salts are the most widely used adjuvants in licensed vaccines with an excellent safety profile.…”

Section: Introductionmentioning

confidence: 99%

Response of BALB/c mice to a monovalent influenza A (H1N1) 2009 split vaccine

Yang

Tang

et al. 2010

Cell Mol Immunol

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“…Thus far, we have generated and evaluated vaccines against seven different influenza virus subtypes in preclinical studies and phase I clinical trials in healthy adults (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Although they replicated and were immunogenic and efficacious in mice and ferrets, the pandemic LAIV (pLAIV) viruses did not replicate efficiently in seronegative healthy adults (18)(19)(20)(21)(22), although some of the pLAIV viruses (e.g., H9N2 and H7N3) induced a robust immune response in vaccinees (21,22).…”

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confidence: 99%

“…AA/60 was provided by MedImmune (Mountain View, CA). The ca viruses were derived as previously described and were manufactured and provided by MedImmune (23)(24)(25)(26)(27)(28)(29). The HA sequences of the reverse genetics derived ca viruses were identical to the wt virus sequences.…”

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confidence: 99%

The Matrix Gene Segment Destabilizes the Acid and Thermal Stability of the Hemagglutinin of Pandemic Live Attenuated Influenza Virus Vaccines

O’Donnell

Vogel

Matsuoka

et al. 2014

J Virol

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The threat of future influenza pandemics and their potential for rapid spread, morbidity, and mortality has led to the development of pandemic vaccines. We generated seven reassortant pandemic live attenuated influenza vaccines (pLAIVs) with the hemagglutinin (HA) and neuraminidase (NA) genes derived from animal influenza viruses on the backbone of the six internal protein gene segments of the temperature sensitive, cold-adapted (ca) A/Ann Arbor/60 (H2N2) virus (AA/60 ca) of the licensed seasonal LAIV. The pLAIV viruses were moderately to highly restricted in replication in seronegative adults; we sought to determine the biological basis for this restriction. Avian influenza viruses generally replicate at higher temperatures than human influenza viruses and, although they shared the same backbone, the pLAIV viruses had a lower shutoff temperature than seasonal LAIV viruses, suggesting that the HA and NA influence the degree of temperature sensitivity. The pH of HA activation of highly pathogenic avian influenza viruses was greater than human and low-pathogenicity avian influenza viruses, as reported by others. However, pLAIV viruses had a consistently higher pH of HA activation and reduced HA thermostability compared to the corresponding wild-type parental viruses. From studies with single-gene reassortant viruses bearing one gene segment from the AA/60 ca virus in recombinant H5N1 or pH1N1 viruses, we found that the lower HA thermal stability and increased pH of HA activation were associated with the AA/60 M gene. Together, the impaired HA acid and thermal stability and temperature sensitivity likely contributed to the restricted replication of the pLAIV viruses we observed in seronegative adults. IMPORTANCEThere is increasing evidence that the HA stability of influenza viruses depends on the virus strain and host species and that HA stability can influence replication, virulence, and transmission of influenza A viruses in different species. We investigated the HA stability of pandemic live attenuated influenza vaccine (pLAIV) viruses and observed that the pLAIV viruses consistently had a less stable HA than the corresponding wild-type influenza viruses. The reduced HA stability and temperature sensitivity of the pLAIV viruses may account for their restricted replication in clinical trials.

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“…We have previously generated live attenuated vaccines against H1N1, H2N2, equine H3N8, H5N1, H6N1, H7N3, H7N7, H7N9, and H9N2 animal influenza viruses and found that these candidate vaccines were safe and efficacious in conferring protection against wild-type viruses in mice and ferrets (23,(27)(28)(29)(30)(31). Several of these vaccines have also been evaluated in phase 1 clinical trials (32)(33)(34)(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets

Baz

Paskel

Matsuoka

et al. 2015

J Virol

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H3N8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. However, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. A live attenuated, cold-adapted (ca) H3N8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin ( We also analyzed human sera against the tl/TX/079/07 H3N8 avian influenza virus and observed low but detectable antibody reactivity in elderly subjects, suggesting that older H3N2 influenza viruses confer some cross-reactive antibody. The latter observation was confirmed in a ferret study. The safety, immunogenicity, and efficacy of the tl/TX/079/07 ca vaccine in mice and ferrets support further evaluation of this vaccine in humans for use in the event of transmission of an H3N8 avian influenza virus to humans. The human and ferret serology data suggest that a single dose of the vaccine may be sufficient in older subjects. IMPORTANCEAlthough natural infection of humans with an avian H3N8 influenza virus has not yet been reported, this influenza virus subtype has already crossed the species barrier and productively infected mammals. Pandemic preparedness is an important public health priority. Therefore, we generated a live attenuated avian H3N8 vaccine candidate and demonstrated that a single dose of the vaccine was highly immunogenic and protected mice and ferrets against homologous and heterologous H3N8 avian viruses. Influenza is an important disease in humans and animals. Influenza A viruses can cross the species barriers intact or following reassortment and have the potential to cause devastating pandemics in humans (1). Pandemic preparedness for influenza has generally been focused on highly pathogenic H5 and H7 avian influenza viruses. However, it is impossible to predict when and where an influenza pandemic will appear, how severe it will be, and which subtype of influenza will emerge as a pandemic strain. Several influenza viruses bearing novel viral gene segments from an animal source have arisen in humans and animals. An example of such an event that underscores the need to consider all influenza virus subtypes was the emergence of the novel H1N1 influenza virus in 2009 despite the ongoing circulation of seasonal H1N1 viruses (2).Avian influenza viruses (AIV) bearing 16 antigenic subtypes of hemagglutinin (HA) and 9 antigenic subtypes of neuraminidase (NA) have been isolated from waterfowl and shorebirds (3, 4), and genetic evidence of H17N10 and H18N11 viruses has been found in bats (5). H3N8 influenza viruses are commonly found in wild birds but are not associated with disease; however, they have been associated with disease outbreaks in dogs (6), horses (7), pigs (8), donkeys (9), and most recently seals (10). Although there have been no known avian H3N8 human cases to date, infections in other mammalian species highlight the ability of this influenza virus subtype to cross the species ...

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Evaluation of Live Attenuated Influenza A Virus H6 Vaccines in Mice and Ferrets

Cited by 55 publications

References 41 publications

Response of BALB/c mice to a monovalent influenza A (H1N1) 2009 split vaccine

Response of BALB/c mice to a monovalent influenza A (H1N1) 2009 split vaccine

The Matrix Gene Segment Destabilizes the Acid and Thermal Stability of the Hemagglutinin of Pandemic Live Attenuated Influenza Virus Vaccines

A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets

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