PLoS One. 2014 Feb 12;9(2):e87962.

Assessment of human immune responses to H7 avian influenza virus of pandemic potential: results from a placebo-controlled, randomized double-blind phase I study of live attenuated H7N3 influenza vaccine.

Rudenko L, Kiseleva I, Naykhin AN, et al.

Department of Virology, Institute of Experimental Medicine, Saint Petersburg, Russia.

 

Abstract

INTRODUCTION: Live attenuated influenza vaccines (LAIVs) are being developed to protect humans against future epidemics and pandemics. This study describes the results of a double-blinded randomized placebo-controlled phase I clinical trial of cold-adapted and temperature sensitive H7N3 live attenuated influenza vaccine candidate in healthy seronegative adults.

OBJECTIVE: The goal of the study was to evaluate the safety, tolerability, immunogenicity and potential shedding and transmission of H7N3 LAIV against H7 avian influenza virus of pandemic potential.

METHODS AND FINDINGS: Two doses of H7N3 LAIV or placebo were administered to 40 randomly divided subjects (30 received vaccine and 10 placebo). The presence of influenza A virus RNA in nasal swabs was detected in 60.0% and 51.7% of subjects after the first and second vaccination, respectively. In addition, vaccine virus was not detected among placebo recipients demonstrating the absence of person-to-person transmission. The H7N3 live attenuated influenza vaccine demonstrated a good safety profile and was well tolerated. The two-dose immunization resulted in measurable serum and local antibody production and in generation of antigen-specific CD4⁺ and CD8⁺ memory T cells. Composite analysis of the immune response which included hemagglutinin inhibition assay, microneutralization tests, and measures of IgG and IgA and virus-specific T cells showed that the majority (86.2%) of vaccine recipients developed serum and/or local antibodies responses and generated CD4⁺ and CD8⁺ memory T cells.

CONCLUSIONS: The H7N3 LAIV was safe and well tolerated, immunogenic in healthy seronegative adults and elicited production of antibodies broadly reactive against the newly emerged H7N9 avian influenza virus.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01511419.

PMID: 24533064

 

SUPPLEMENTARY

One of the most crucial factors for licensing new influenza vaccines is the level of vaccine immunogenicity, as detected by standard assays accepted by regulatory agents in various places.

Regulatory requirements for live influenza vaccine (LAIV), in effect since 1978 considered induction of serum antibodies revealed by the HAI assay as the only criterion for LAIV immunogenicity [1]. Regulatory requirements for live influenza vaccine (LAIV), in effect since 1978 considered induction of serum antibodies revealed by the HAI assay as the only criterion for LAIV immunogenicity [1]. This approach was based on anti–influenza immunity data regarding inactivated influenza vaccines (IIV). From the late 1960s – early 1970s antibodies circulating in the blood were the only known factor that correlated with protection. Since then, our knowledge about anti–influenza immunity has greatly increased. It has been demonstrated that LAIV induces humoral and cellular immune protection locally, at the initial site of infection, the respiratory tree, while IIV primary induces antibodies circulating in the blood [2]. The generation of local B and T cellular immune memory appears to be the principal anti–influenza protection mechanism with LAIV [3] while the serum immune responses are recognized as a good correlate of vaccine protection for IIV. WHO considers important to assess the potential efficacy of LAIV by measuring not only humoral response but also innate, mucosal and cellular immune responses [4].

tab1

For inactivated vaccines, HAI titers are an accepted correlate of protection. However, HAI titers do not appear to correlate with protection against influenza by LAIV [5] yet for avian LAIV directed against pandemic strains where clinical efficacy cannot be measured in pre–pandemic period, a multiplicity of assay may reveal a better correlate.

In accordance with WHO recommendations, to fully characterize the H7N3 vaccine we tested the sera from all the volunteers using several additional assays, including microneutralization and detection of serum IgG and IgA antibodies as well as mucosal IgA antibody, by ELISA. Cumulative data on antibody immune responses showed that 25/29 (86.2%) of evaluable vaccinated subjects had serum and/or mucosal antibodies generated because of vaccination (Table 1).

Our study also shows the cross–reactive potential of the H7N3 LAIV strain against an H7N9 virus. Sera from some of the H7N3–vaccinated subjects elicited heterosubtypic antibodies able to neutralize newly emerged H7N9 virus, which caused considerable public health impact in China in the spring of 2013.

 

References

  1. Requirements for influenza vaccine (inactivated) and for influenza vaccines (live). WHO Expert Committee on Biological Standardization. Thirtieth report, Annex 3. Geneva, World Health Organization (1979) (WHO Technical Report Series, No. 638). Available from: http://www.who.int/biologicals/publications/trs/areas/vaccines/influenza/WHO_TRS_638_InfluenzaA3.pdf. Accessed 26 November 2014.
  2. Points to consider on the development of live attenuated influenza vaccines (EMEA/CPMP/BWP/2289/01) (2003) Available from: http://www.tga.gov.au/pdf/euguide/bwp228901en.pdf. Accessed 26 November 2014.
  3. He XS, Holmes TH, Zhang C, Mahmood K, Kemble GW et al. (2006) Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. J Virol 80(23): 11756–117566.
  4. WHO recommendations to assure the quality, safety, and efficacy of influenza vaccines (human, live attenuated) for intranasal administration. Final Expert Committee on Biological Standardization (2009). Available from: http://www.who.int/biologicals/areas/vaccines/influenza/Influenza_vaccines_final_14MAY_2010.pdf. Accessed 26 November 2014.
  5. Mallory RM, Malkin E, Ambrose CS, Bellamy T, Shi L et al. (2010) Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials. PLoS One 5(10): e13755. doi: 10.1371/journal.pone.0013755.

 

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