Memory Immune Responses against Pandemic (H1N1) 2009 Influenza Virus Induced by a Whole Particle Vaccine in Cynomolgus Monkeys Carrying Mafa-A1*052∶02

Abstract

We made an H1N1 vaccine candidate from a virus library consisting of 144 ( = 16 HA×9 NA) non-pathogenic influenza A viruses and examined its protective effects against a pandemic (2009) H1N1 strain using immunologically naïve cynomolgus macaques to exclude preexisting immunity and to employ a preclinical study since preexisting immunity in humans previously vaccinated or infected with influenza virus might make comparison of vaccine efficacy difficult. Furthermore, macaques carrying a major histocompatibility complex class I molecule, Mafa-A1*052∶02, were used to analyze peptide-specific CD8+ T cell responses. Sera of macaques immunized with an inactivated whole particle formulation without addition of an adjuvant showed higher neutralization titers against the vaccine strain A/Hokkaido/2/1981 (H1N1) than did sera of macaques immunized with a split formulation. Neutralization activities against the pandemic strain A/Narita/1/2009 (H1N1) in sera of macaques immunized twice with the split vaccine reached levels similar to those in sera of macaques immunized once with the whole particle vaccine. After inoculation with the pandemic virus, the virus was detected in nasal samples of unvaccinated macaques for 6 days after infection and for 2.67 days and 5.33 days on average in macaques vaccinated with the whole particle vaccine and the split vaccine, respectively. After the challenge infection, recall neutralizing antibody responses against the pandemic virus and CD8+ T cell responses specific for nucleoprotein peptide NP262-270 bound to Mafa-A1*052∶02 in macaques vaccinated with the whole particle vaccine were observed more promptly or more vigorously than those in macaques vaccinated with the split vaccine. These findings demonstrated that the vaccine derived from our virus library was effective for pandemic virus infection in macaques and that the whole particle vaccine conferred more effective memory and broader cross-reactive immune responses to macaques against pandemic influenza virus infection than did the split vaccine.

Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates

“…We have used macaques as well as mice to reveal that inactivated whole-particle vaccines were more effective against H5N1 highly pathogenic avian influenza virus and pandemic (H1N1) 2009 virus than were ether-split vaccines (16,53). Therefore, we prepared the H7N9 whole-particle vaccine selected from our virus library (19), in which vaccine strains were efficiently propagated in embryonated eggs without adaptation to minimize the time required for vaccine production.…”

“…However, the frequency of emergence of a resistant virus has not been determined in human patients. Therefore, assessment of the efficacy of NA inhibitors and of an emerging virus resistant to NA inhibitors in macaques is required under controlled conditions with administration after regulated time points and without coexisting complications since cynomolgus macaques showed symptoms similar to those seen in humans infected with influenza virus (15)(16)(17)(18).…”

Pathogenicity of Pandemic H1N1 Influenza A Virus in Immunocompromised Cynomolgus Macaques

“…The pandemic influenza virus A/Narita/1/2009 (H1N1) pdm (kindly provided by Dr. Takato Odagiri, National Institute of Infectious Disease (NIID), Japan. NCBI taxonomy database ID: 645520) [59,60] was cultured twice in embryonated eggs in NIID and once in MDCK cells at Shiga University of Medical Sciences.…”

Discovery of novel MHC-class I alleles and haplotypes in Filipino cynomolgus macaques (Macaca fascicularis) by pyrosequencing and Sanger sequencing

“…Many of these diseases and treatment outcomes are influenced by polymorphisms of the major histocompatibility complex (MHC), a genomic region that encodes the MHC transplantation and immune regulatory molecules Shiina et al 2004). In this regard, information on the diversity of the MHC alleles and haplotypes may provide an internal genetic control to better define the factors of disease susceptibility and immunity and help to maximize the power of the small study sizes and minimize a priori bias and the effect of heterozygosity in the macaque disease study groups (Arikata et al 2012;Ericsen et al 2014;Vallender 2014).…”