Development of live attenuated influenza vaccines against pandemic influenza strains

Abstract

Avian and animal influenza viruses can sporadically transmit to humans, causing outbreaks of varying severity. In some cases, further human-to-human virus transmission does not occur, and the outbreak in humans is limited. In other cases, sustained human-to-human transmission occurs, resulting in worldwide influenza pandemics. Preparation for future pandemics is an important global public health goal. A key objective of preparedness is to gain an understanding of how to design, test, and manufacture effective vaccines that could be stockpiled for use in a pandemic. This review summarizes results of an ongoing collaboration to produce, characterize, and clinically test a library of live attenuated influenza vaccine strains (based on Ann Arbor attenuated Type A strain) containing protective antigens from influenza viruses considered to be of high pandemic potential.

Keywords::

• intranasal influenza vaccine
• LAIV
• pandemic influenza vaccine

Acknowledgements

We would like to thank the volunteers who participated in these studies and the clinical and laboratory staff that made the studies possible.

Financial & competing interests disclosure

KC is an employee of AstraZeneca, HJ is an employee of MedImmune; both may hold stock or stock options in AstraZeneca, the parent company of MedImmune. CL is a member of the Executive Committee for a Cooperative Research and Development Agreement between NIH and MedImmune. KT has no competing interests to declare. The influenza pandemic vaccine program is conducted as part of a Cooperative Research and Development Agreement between MedImmune and the Laboratory of Infectious Diseases, NIAID. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The 2009 H1N1pdm LAIV studies were funded in whole or in part with Federal funds from the HHS Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority under Contract HHS0100200900021. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript. Editorial assistance was provided by DeRocco SE and Fincke JE of Complete Healthcare Communications, Inc. (Chadds Ford, PA) and was funded by MedImmune.

Key issues

• Live attenuated influenza vaccine (LAIV) has attributes that would be potentially advantageous in a pandemic setting. For example, relatively high efficacy (60–90%) observed after a single dose of LAIV in previously unvaccinated children is an important consideration in a pandemic setting, when most persons of all ages could be immunologically naive to the emergent virus. Demonstrated cross-protection by LAIV against antigenically drifted strains could be important if the pandemic virus undergoes antigenic drift. In addition, the potential for induction of innate antiviral immunity and local mucosal immune responses by live vaccines, such as nasally administered LAIV, could provide protection against pandemic influenza during the period in which adaptive immunity develops after vaccination. Finally, the high yield of LAIV in eggs and ease of nasal administration make pandemic LAIV (pLAIV) a particularly desirable pandemic vaccine.

• Studies in adults of pLAIV bearing HA and NA from H2, H5, H6, H7 and H9 influenza viruses indicated that the vaccine strains were attenuated and were detectable in nasal samples at low levels for 1–2 days after vaccination. The proportion of adults who developed an antibody response to pLAIV in any assay varied for the different strains tested and ranged from 24 to 100% for pLAIV formulated at standard seasonal LAIV potency. Serum hemagglutination inhibition (HAI) response rates ranged from 0 to 92% for pLAIV. By comparison, the serum HAI response rate of seronegative adults was approximately 12–14% to human type A strains in seasonal LAIV and 15% to monovalent H1N1 2009pdm LAIV. Thus, the modest serum antibody response rates measured for pLAIV are consistent with experience with seasonal LAIV.

• Additional studies with H5 pLAIV indicated that even in the absence of measurable shedding and/or immune responses, immunological priming occurs after vaccination with pLAIV, resulting in rapid production of high titers of cross-reactive serum HAI antibodies upon subsequent vaccination with pandemic inactivated subvirion influenza vaccine.

• During the 2009 H1N1 pandemic in the USA, pLAIV was widely used and was safe, immunogenic and effective. Although the immunogenicity of H1N1 2009pdm LAIV was characteristically modest, effectiveness was 61% (95% CI: 12–82) in persons 2–49 years of age and 82% (95% CI: 14–96) in children 2–9 years of age.

• In summary, results of clinical trials indicate that pLAIV and seasonal LAIV have similar safety profiles in adults. The modest serum antibody response rates measured for pLAIV are consistent with seasonal LAIV antibody responses.

• The clinical profile of LAIV, its high manufacturing yields and ease of nasal administration highlight the unique role that pLAIV can play in a pandemic setting.

Notes