Safety and immunogenicity of a replication-deficient H5N1 influenza virus vaccine lacking NS1

Highlights

• First in humans study with a live attenuated pandemic delNS1-H5N1 vaccine.

• Significant serum antibody titers as measured by HAI and MNA after two immunizations.

• DelNS1-H5N1 well tolerated and safe in healthy male and female participants.

• No vaccine virus re-isolated in participants after one immunization.

Abstract

Background

Traditional inactivated influenza vaccines are the type of vaccines that were most frequently developed for immunization against the highly pathogenic avian H5N1 influenza virus. However, clinical trials with inactivated influenza vaccines for H5N1 indicated that high doses and at least two immunizations are required for an effective immune response (Nicholson et al., 2001; Treanor, Campbell et al., 2006; Treanor, Schiff et al., 2006; Ehrlich et al., 2008). We investigated the safety and immunogenicity of a live attenuated H5N1 vaccine (delNS1-H5N1) lacking the interferon antagonist nonstructural protein 1 (NS1).

Methods

We conducted a double-blind, placebo-controlled, phase 1 study in healthy adult participants who were randomly assigned at a 2:1 ratio to receive two immunizations of delNS1-H5N1 vaccine at 6.8 log10 50% tissue culture infectious doses (TCID₅₀)/subject or 7.5 log10 TCID₅₀/subject, or placebo.

Results

Intranasal vaccination with the live attenuated delNS1-H5N1 vaccine was safe and well tolerated. The most common adverse events identified were symptoms associated with mild influenza infections, such as increased body temperature (>37.0 °C), pharyngeal erythema, rhinitis and throat irritation, and were reported within 7 days after the first immunization. delNS1-H5N1 was able to induce significant vaccine-specific serum antibody titers even at the lower dose level of 6.8 log10 TCID₅₀/subject. Seroconversion occurred in 75% of study participants after only one immunization with 7.5 log10 TCID₅₀/subject. Vaccine-specific local IgA responses were observed in 41.7% of individuals that showed serum antibody responses after 2nd immunization.

Conclusions

We show that vaccination with a live attenuated H5N1 influenza vaccine lacking NS1 is safe and induces significant levels of vaccine-specific antibodies even after one immunization. The safety and immunogenicity data indicate that delNS1-H5N1 has the potential to fulfil the unmet need for an effective influenza vaccine in pandemic situations. (ClinicalTrials.gov identifier NCT03745274).

Introduction

Avian influenza is a highly contagious disease caused by infections with influenza A viruses that primarily circulate in domestic and wild birds but can also infect humans. Avian influenza has continued to occur since the first recorded direct bird-to-human transmission of a highly pathogenic avian influenza A(H5N1) virus in Hong Kong in 1997 [2]. Although isolated human-to-human transmission has been reported in several countries and H5N1 continuously evolves, creating new potentially pathogenic drift variants [3], these viruses have not yet acquired efficient transmissibility among humans [4], [5], [6]. The number of human infections with H5N1 has been declining over the past years [7], however, the high pathogenicity of the virus, the observed high mortality of infected patients, and the unprecedented spread of H5N1 viruses have raised concerns that conditions are developing for the generation of a new pandemic virus.

In recent years, live attenuated influenza vaccines (LAIVs) have become increasingly attractive, following the WHO’s recognition of LAIVs to increase the production capacity for pandemic vaccines [8]. LAIVs are attractive pandemic vaccine candidates because they mimic natural infection by replicating primarily in the upper respiratory tract and inducing mucosal IgA antibody responses [9], [10], [11]. LAIV technologies using vaccine strains have the potential to reassort with circulating influenza viruses, which must be considered. A LAIV that is replication-deficient would mitigate the potential for reassortment while offering the advantages of the LAIV approach.

We have developed a novel type of live attenuated influenza vaccine by deleting the interferon antagonist NS1 from influenza virus IVR-116. The 5 internal genes from IVR-116 were co-transfected with the HA, NA and M gene from the pandemic H5N1 virus (A/Vietnam/1203/04), resulting in a live attenuated vaccine virus termed delNS1-H5N1.

Here, we report the safety and immunogenicity after one and two immunizations of a live attenuated delNS1-H5N1 influenza vaccine in healthy male and female humans.