scholarly journals Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 86 ◽  
Author(s):  
Thomas A. Hilimire ◽  
Aitor Nogales ◽  
Kevin Chiem ◽  
Javier Ortego ◽  
Luis Martinez-Sobrido
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Infection ◽  
Vaccination Campaign ◽  
The Elderly ◽  
Antiviral Responses ◽  
Live Attenuated Influenza Vaccine ◽  
Ann Arbor ◽  
Health Burdens

Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.

scholarly journals A single amino acid substitution in PB1 of pandemic H1N1 with A/Ann Arbor/6/60 master donor virus mutations as a novel live-attenuated influenza virus vaccine

2022 ◽  
Author(s):  
Aitor Nogales ◽  
John Steel ◽  
Wen-Chun Liu ◽  
Anice C Lowen ◽  
Laura Rodriguez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Guinea Pigs ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Infection ◽  
The United States ◽  
Single Amino Acid ◽  
Temperature Sensitive ◽  
Ann Arbor ◽  
The U.S

Influenza A viruses (IAV) remain emerging threats to human public health. Live-attenuated influenza vaccines (LAIV) are one of the most effective prophylactic options to prevent disease caused by influenza infections. However, licensed LAIV remain restricted for use in 2- to 49-year old healthy and non-pregnant people. Therefore, development of LAIV with increased safety, immunogenicity, and protective efficacy is highly desired. The United States (U.S.) licensed LAIV is based on the master donor virus (MDV) A/Ann Arbor/6/60 H2N2 backbone, which was generated by adaptation of the virus to growth at low temperatures. Introducing the genetic signature of the U.S. MDV into the backbone of other IAV strains resulted in varying levels of attenuation. While the U.S. MDV mutations conferred an attenuated phenotype to other IAV strains, the same amino acid changes did not significantly attenuate the pandemic A/California/04/09 H1N1 (pH1N1) strain. To attenuate pH1N1, we replaced the conserved leucine at position 319 with glutamine (L319Q) in PB1 and analyzed the in vitro and in vivo properties of pH1N1 viruses containing either PB1 L319Q alone or in combination with the U.S. MDV mutations using two animal models of influenza infection and transmission, ferrets and guinea pigs. Our results demonstrated that L319Q substitution in the pH1N1 PB1 alone or in combination with the mutations of the U.S. MDV resulted in reduced pathogenicity (ferrets) and transmission (guinea pigs), and an enhanced temperature sensitive phenotype. These results demonstrate the feasibility of generating an attenuated MDV based on the backbone of a contemporary pH1N1 IAV strain.

scholarly journals A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Andrew Smith ◽  
Laura Rodriguez ◽  
Maya El Ghouayel ◽  
Aitor Nogales ◽  
Jeffrey M. Chamberlain ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
H1n1 Virus ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Temperature Sensitive ◽  
Live Attenuated Influenza Vaccine ◽  
Cell Immunity

ABSTRACT Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains. IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

scholarly journals Severity of heterosubtypic influenza virus infection in ferrets is reduced by live attenuated influenza vaccine

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Anthony C. Marriott ◽  
Karen E. Gooch ◽  
Phillip J. Brown ◽  
Kathryn A. Ryan ◽  
Nicola J. Jones ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Virus Infection ◽  
H3n2 Virus ◽  
Live Attenuated Influenza Vaccine ◽  
Inactivated Vaccines ◽  
Ifn Γ ◽  
Cellular Immune

AbstractLive attenuated influenza vaccine (LAIV) is widely used to protect humans from seasonal influenza infection, particularly in children. In contrast to inactivated vaccines, the LAIV can induce both mucosal and cellular immune responses. Here we show that a single dose of monovalent H1N1pdm09-specific LAIV in the ferret model is fully protective against a subsequent wild-type H1N1pdm09 challenge, and furthermore reduces the severity of disease following challenge with a different influenza A subtype (H3N2). The reduced severity comprised reductions in weight loss and fever, as well as more rapid clearance of virus, compared to non-vaccinated H3N2-challenged ferrets. No H3N2-neutralizing antibodies were detected in vaccinated ferret sera. Rather, heterosubtypic protection correlated with interferon-gamma+ (IFN-γ+) T-cell responses measured in peripheral blood and in lung lymphocytes. The IFN-γ+ cells were cross-reactive to H3N2 virus even when obtained from vaccinated animals that had never been exposed to H3N2 virus. We believe this study provides compelling evidence that the LAIV can provide a significant reduction in infection and symptoms when challenged with heterosubtypic influenza strains not included in the LAIV, highlighting the importance of cross-reactive T-cells in the design of a universal influenza vaccine.

scholarly journals Effectiveness of seasonal influenza vaccine for adults and children in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2015/16 end-of-season results

2016 ◽  
Vol 21 (38) ◽  
Author(s):  
Richard Pebody ◽  
Fiona Warburton ◽  
Joanna Ellis ◽  
Nick Andrews ◽  
Alison Potts ◽  
...  
Keyword(s):  
Primary Care ◽  
United Kingdom ◽  
Influenza Vaccine ◽  
Influenza A ◽  
Immunisation Programme ◽  
Influenza B ◽  
Live Attenuated Influenza Vaccine ◽  
The United Kingdom ◽  
Influenza A H1n1 ◽  
The Uk

The United Kingdom (UK) is in the third season of introducing universal paediatric influenza vaccination with a quadrivalent live attenuated influenza vaccine (LAIV). The 2015/16 season in the UK was initially dominated by influenza A(H1N1)pdm09 and then influenza of B/Victoria lineage, not contained in that season’s adult trivalent inactivated influenza vaccine (IIV). Overall adjusted end-of-season vaccine effectiveness (VE) was 52.4% (95% confidence interval (CI): 41.0–61.6) against influenza-confirmed primary care consultation, 54.5% (95% CI: 41.6–64.5) against influenza A(H1N1)pdm09 and 54.2% (95% CI: 33.1–68.6) against influenza B. In 2–17 year-olds, adjusted VE for LAIV was 57.6% (95% CI: 25.1 to 76.0) against any influenza, 81.4% (95% CI: 39.6–94.3) against influenza B and 41.5% (95% CI: −8.5 to 68.5) against influenza A(H1N1)pdm09. These estimates demonstrate moderate to good levels of protection, particularly against influenza B in children, but relatively less against influenza A(H1N1)pdm09. Despite lineage mismatch in the trivalent IIV, adults younger than 65 years were still protected against influenza B. These results provide reassurance for the UK to continue its influenza immunisation programme planned for 2016/17.

scholarly journals Vaccine effectiveness for influenza in the elderly in welfare nursing homes during an influenza A (H3N2) epidemic

2000 ◽  
Vol 125 (2) ◽  
pp. 393-397 ◽  
Author(s):  
Y. DEGUCHI ◽  
Y. TAKASUGI ◽  
K. NISHIMURA
Keyword(s):  
Nursing Homes ◽  
Influenza Vaccine ◽  
Influenza A ◽  
Hospital Admissions ◽  
Influenza Virus Infection ◽  
Severe Infection ◽  
The Elderly ◽  
Trivalent Influenza Vaccine ◽  
Homes For The Elderly ◽  
Vaccine Effect

Influenza vaccine effect on the occurrence and severity of influenza virus infection in a population residing in nursing homes for the elderly was studied as a cohort study during an influenza A (H3N2) epidemic in Japan. Of 22462 individuals living in 301 welfare nursing homes, 10739 voluntarily received inactivated, sub-unit trivalent influenza vaccine in a programme supported by the Osaka Prefectural Government. There were statistically significantly fewer cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort compared to the unvaccinated controls. No serious adverse reactions to vaccination were recorded. Thus influenza vaccination is effective for preventing influenza disease in persons aged 65 years and over, and should be an integral part of the care of this population residing in nursing homes.

scholarly journals Adjuvanted Influenza Vaccines Elicits Higher Antibody Responses against the A(H3N2) Subtype than Non-Adjuvanted Vaccines

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 704
Author(s):  
Laura Sánchez de Prada ◽  
Iván Sanz Muñoz ◽  
Javier Castrodeza Sanz ◽  
Raúl Ortiz de Lejarazu Leonardo ◽  
José María Eiros Bouza
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
Seasonal Influenza ◽  
The Elderly ◽  
Antibody Responses ◽  
Serological Response ◽  
Serum Samples ◽  
H3n2 Subtype ◽  
Serological Studies ◽  
Vaccination Campaigns

Background: vaccination is the best approach to prevent influenza infections so far. Serological studies on the effect of different vaccine types are important to address vaccination campaigns and protect our population. In our study, we compared the serological response against influenza A subtypes using the non-adjuvanted influenza vaccine (NAIV) in adults and the elderly and the adjuvanted influenza vaccine (AIV) in the elderly. Methods: We performed a retrospective analysis by hemagglutination inhibition assay (HI) of serum samples right before and 28 days after seasonal influenza vaccination during the 1996–2017 seasons. Conclusions: The AIV presents better performance against the A(H3N2) subtype in the elderly whereas the NAIV induces a better response against A(H1N1)pdm09 in the same group.

scholarly journals Occurrence of influenza B/Hong Kong-Like strains in Brazil, during 2002

2003 ◽  
Vol 45 (1) ◽  
pp. 51-52 ◽  
Author(s):  
Terezinha Maria de Paiva ◽  
Maria Akiko Ishida ◽  
Maria Gisele Gonçalves ◽  
Margareth Aparecida Benega ◽  
Maria Candida Oliveira de Souza ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Hong Kong ◽  
Influenza A ◽  
Vaccination Campaign ◽  
Age Groups ◽  
Respiratory Illness ◽  
The Elderly ◽  
Influenza B ◽  
Surveillance Period ◽  
Influenza A H1n1

Through the influenza virus surveillance from January to October 2002, influenza B/Hong Kong-like strains circulating in the Southeast and Centre East regions of Brazil have been demonstrated. This strain is a variant from B/Victoria/02/88 whose since 1991 and until recently have been isolated relatively infrequently and have been limited to South-Eastern Asia. A total of 510 respiratory secretions were collected from patients 0 to 60 years of age, with acute respiratory illness, living in the Southeast and Centre East regions of Brazil, of which 86 (17.13%) were positive for influenza virus. Among them 12 (13.95%) were characterized as B/Hong Kong/330/2001; 3 (3.49%) as B/Hong Kong/1351/2002 a variant from B/Hong Kong/330/2001; 1 (1.16%) as B/Sichuan/379/99; 1 (1.16%) as B/Shizuoka/5/2001, until now. The percentages of cases notified during the surveillance period were 34.88%, 15.12%, 15.12%, 4.65%, 15.12%, 13.95%, in the age groups of 0-4, 5-10, 11-15, 16-20, 21-30, 31-50, respectively. The highest proportion of isolates was observed among children younger than 4 years but serious morbidity and mortality has not been observed among people older than 65 years, although B influenza virus component for vaccination campaign 2002 was B/Sichuan/379/99 strain. This was probably due to the elderly protection acquired against B/Victoria/02/88. In addition, in influenza A/Panama/2007/99-like (H3N2) strains 22 (25.58%) were also detected, but influenza A(H1N1) has not been detected yet.

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