An open‐label phase I trial of a live attenuated H2N2 influenza virus vaccine in healthy adults

Talaat, Kawsar R.; Karron, Ruth A.; Liang, Philana H.; McMahon, Bridget A.; Luke, Catherine J.; Thumar, Bhagvanji; Chen, Grace L.; Min, Ji Young; Lamirande, Elaine W.; Jin, Hong; Coelingh, Kathy L.; Kemble, George; Subbarao, Kanta

doi:10.1111/j.1750-2659.2012.00350.x

Cited by 39 publications

(32 citation statements)

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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%

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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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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“…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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“…O'Donnell et al [61] showed that 6/2 reassortants of A/Ann Arbor/6/1960 CA (H2N2) master strain with viruses of H1N1, H3N2, H2N2, H6N1, H7N3, H9N2, and H5N1 subtypes have an elevated pH of HA fusion and decreased stability to low pH and elevated temperatures compared to the corresponding epidemic viruses. Clinical trials performed with some of 6/2 reassortants showed their restricted replication in the respiratory tract of seronegative adult volunteers [58,62,63]. The authors of these papers have found that the decreased stability of the studied reassortants is connected with the nature of the M gene of A/Ann Arbor/6/1960 CA master strain, but the exact mechanism of this phenomenon was not discussed.…”

Section: Cell-based Influenza Vaccinesmentioning

confidence: 99%

“…Thus, the pre-pandemic vaccine produced from the virus of H2N2 subtype (FluMist®) showed the restricted virus replication in the URT (24%) and immune response in only 24% of participants [58]. The vaccine strain used in this study was the master strain A/Ann Arbor/6/1960 (H2N2) that is used as a backbone for the seasonal vaccine strains.…”

Section: Effect Of Influenza Virus Stability On the Quality Of Live Amentioning

confidence: 99%

Influenza vaccines manufacturing in continuous cell lines: problems and solutions

Romanova¹

2017

Microbiology Independent Research Journal (MIR Journal)

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In order to decrease the morbidity and mortality caused by seasonal influenza outbreaks, several hundred million vaccine doses are produced worldwide each year. The predominant substrate for the production of the influenza vaccine today is fertilized hen's eggs. The substitution of the technology based on living organisms by the cell culture-based process offers many advantages, including easier scalability and reduced dependence on the availability of eggs. The African green monkey kidney and Madin Darby canine kidney cell lines support the efficient growth of influenza viruses of different subtypes and, therefore, are considered to be the two most promising alternative substrates for the production of the human influenza vaccine.However, the pH of endosomes in both of these cell lines is higher than the pH essential for triggering a conformational change of the hemagglutinin (HA) of human influenza viruses, which enables the viral-cellular membrane fusion. This mismatch gives rise to mutations in the HA that lead to an increase of the optimum pH of HA conformational change. As of a result of these mismatches, the HA, and consequently the whole virus, has reduced stability to low pH and elevated temperatures. The production of a vaccine from less stable virus will lead to an elevated HA content in the low pH conformation that can affect the safety, potency, infectivity, and protective efficacy of the final inactivated and live attenuated influenza vaccines.The main limitations of the cell line-based influenza vaccine technology and the possibilities to preserve the viral stability over the course of influenza vaccine production are discussed in the review.

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An open‐label phase I trial of a live attenuated H2N2 influenza virus vaccine in healthy adults

Cited by 39 publications

References 32 publications

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

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

Influenza vaccines manufacturing in continuous cell lines: problems and solutions

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