Safety, immunogenicity and infectivity of new live attenuated influenza vaccines

Abstract

Live attenuated influenza vaccines (LAIVs) are believed to be immunologically superior to inactivated influenza vaccines, because they can induce a variety of adaptive immune responses, including serum antibodies, mucosal and cell-mediated immunity. In addition to the licensed cold-adapted LAIV backbones, a number of alternative LAIV approaches are currently being developed and evaluated in preclinical and clinical studies. This review summarizes recent progress in the development and evaluation of LAIVs, with special attention to their safety, immunogenicity and infectivity for humans, and discusses their perspectives for the future.

Keywords:

• immunogenicity
• licensure criteria
• live attenuated influenza vaccine
• pandemic influenza
• safety
• seasonal influenza
• vaccine virus shedding

Financial & competing interests disclosure

I Isakova-Sivak is an employee of the Institute of Experimental Medicine, Russia, and is supported by the Russian Scientific Foundation (Grant No 14-15-00034). L Rudenko is an employee of the Institute of Experimental Medicine, Russia, and is a non-executive director of BioDiem Ltd; she is also supported by the Russian Scientific Foundation (Grant No 14-15-00034). Writing assistance was utilized in the preparation of this manuscript in the form of editing by P Butler, Antwerp (Belgium), and this was funded by WHO. E Grigorieva from the Institute of Experimental Medicine, Russia, assisted with data collection for the manuscript; this was funded for by the Russian Scientific Foundation (Grant No 14-15-00034). 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.

Key issues

• Currently licensed cold-adapted live attenuated influenza vaccine (LAIV) backbones have been in use for almost three decades, and new pandemic LAIV candidates based on these backbones exhibited safety profile similar to that of seasonal LAIVs, although they were less infective and induced weaker immune responses in humans. Nevertheless, recent studies revealed that priming with pandemic LAIV induced a long-lasting B-cell immunological memory in humans against antigenically related influenza virus, which was characterized by more prompt and vigorous antibody production to a single suboptimal dose of inactivated vaccine given 19–50 months later.

• Following the success of the licensed LAIVs used in different age groups, new cold-adapted backbones are being developed and evaluated throughout the world. All of them were intensively studied in animal models, and seasonal and pandemic LAIV strains prepared on their basis demonstrated good safety, immunogenicity and protective efficacy. However, only limited data are available on the performance of these LAIVs in clinical trials.

• In recent years, a number of alternative LAIVs generated by genetic engineering approaches have been developed and evaluated in animal models. These LAIVs are designed to provide adequate protection to all at-risk groups, who cannot safely receive the licensed LAIVs (e.g., pregnant women, children or adolescents on long-term aspirin treatment, people who are allergic to eggs, immunosuppressed people, etc.). However, it is unlikely that any of the new LAIVs will be licensed for human use within the next decade, because intensive clinical trials are needed to establish their safety and efficacy profiles in different age groups.

• In past two decades, attempts have been made to develop universal influenza vaccine, which would induce broad protection against different types and subtypes of the influenza virus. However, there is yet no suitable vaccine candidate that satisfies all requirements (safety, immunogenicity, genetic stability and the capability to scale up production). Both licensed and alternative LAIVs should be evaluated as a promising platform for designing a new generation of the universal vaccine.

• LAIVs also represent a promising platform for the development of virus-vectored vaccines due to the ability to manipulate the genetic information of the influenza virus genome. Designing new generation of vectored vaccines based on LAIV viruses with demonstrated huge safety record may allow in a near future the development of vaccines against many kinds of viral and bacterial infections.