Insights into current clinical research on the immunogenicity of live attenuated influenza vaccines

ABSTRACT

Introduction: Live attenuated influenza vaccines (LAIVs) have been in use for more than three decades and are now licensed in many countries. There is evidence that LAIVs can have greater efficacy than inactivated influenza vaccines, especially against mismatched influenza, however, in recent years, a number of trials have found a lack of LAIV efficacy, mainly in relation to the H1N1 virus.

Areas covered: In this review, we summarize the results of clinical research published in the past 5 years on the immunogenicity of LAIVs, with special attention to the mechanisms of establishing protective immunity and some factors that may influence immunogenicity and efficacy.

Expert opinion: A number of recent clinical studies confirmed that the immune responses to LAIVs are multifaceted, involving different immune mechanisms. These trials suggest that the intrinsic replicative properties of each LAIV component should be taken into account, and the precise effects of adding a fourth vaccine strain to trivalent LAIV formulations are still to be identified. In addition, new data are emerging regarding the impact of pre-vaccination conditions, such as preexisting immunity or concurrent asymptomatic viral and bacterial respiratory infections, on LAIV immunogenicity, suggesting the importance of monitoring them during clinical trials or vaccination campaigns.

KEYWORDS:

• Live attenuated influenza vaccine
• clinical trial
• immunogenicity
• antibody immune response
• cell-mediated immune response
• correlate of protection

Article highlights

• There is a need to identify the precise effects of adding a fourth vaccine strain to trivalent LAIV formulations. The convincing data on better LAIV performance relative to IIV was obtained in clinical studies of trivalent LAIVs, and there is a lack of comprehensive comparative studies of the quadrivalent versus the trivalent formulation in clinical settings.

• More data are needed on the possible impacts of repeated LAIV vaccination on vaccine performance in settings with widespread LAIV use, given the accumulating data on the negative effects of repeated immunization with IIVs.

• Vaccine strains need to be more carefully selected for the development of LAIV strains than for IIV. The antigenicity should be similar to the recommended strain; however, the virus should also replicate well in hNEC cells, to ensure that it will replicate in the upper respiratory tract, and that competition between vaccine strains will be minimized.

• There is significant variation in the methods of sample collection for studies of LAIV shedding (sampling procedure, timing post-vaccination, sample processing, etc.), which makes it difficult to compare the results of different studies. In addition, assessment of immune responses is based on different timing and procedures, which also makes comparison of performance of LAIVs in different studies difficult. All these assays should be harmonized to ensure that the data obtained are comparable.

• LAIV shedding is dependent on the baseline immunity, and it is speculated that the efficacy of LAIV is reduced in seropositive subjects. However, if the vaccine virus does not replicate, the wild-type virus should also not replicate.

• New data are emerging regarding the impact of pre-vaccination conditions on shedding (and immunogenicity of LAIV). All these data need to be taken into account when conducting clinical trials or vaccination campaigns. For example, testing for concurrent asymptomatic viral and bacterial respiratory infections is warranted.

• Although there has been an increase in the number of controlled human challenge studies of different vaccines and antivirals, such studies for LAIVs are lacking. These studies would help to identify the precise correlates of protection, and in particular to evaluate the vaccine’s immunogenicity and efficacy in adults with pre-existing immunity.

Acknowledgments

We thank Dr. Patricia Butler for editorial assistance.

Declaration of interest

I Isakova-Sivak, L Rudenko and E Grigorieva are all funded by the Russian Ministry of Science and Education program (0557-2019-0003). 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was carried out with financial support from Ministry of Science and Higher Education of the Russian Federation, Program ID [0557-2019-0003].