Abstract
BackgroundAlthough DNA plasmid and virus-like particle (VLP) vaccines have been individually tested against highly pathogenic avian influenza (HPAI) H5N1 viruses, the combination of both vaccines into a heterologous prime-boost strategy against HPAI H5N1 viruses has not been reported before.Methodology/Principal FindingsWe constructed DNA plasmid encoding H5HA (A/Shenzhen/406H/06, subclade 2.3.4) and generated VLP expressing the same H5HA and N1NA. We then compared neutralizing antibody responses and immune protection elicited with heterologous DNA-VLP, homologous DNA-DNA and VLP-VLP prime-boost strategies against HPAI H5N1 viruses in mice. We demonstrate that DNA-VLP elicits the highest neutralizing antibody titers among the three prime-boost strategies, whereas DNA-DNA elicits higher neutralizing antibody titers than VLP-VLP. We show that although all three prime-boost strategies protect mice from death caused by 10 MLD50 of homologous and heterologous H5N1 challenge, only DNA-VLP and DNA-DNA protect mice from infection as manifested by no weight loss and no lung pathology. In addition, we show that although DNA-VLP and DNA-DNA protect mice from death caused by 1,000 MLD50 of homologous H5N1 challenge, only DNA-VLP protects mice from infection. Moreover, we show that after 1,000 MLD50 of heterologous H5N1 challenge, while all mice in PBS, VLP-VLP and DNA-DNA died, 3 of 6 mice in DNA-VLP actually survived. Finally, we show that DNA-VLP completely protects mice from infection after 1,000 MLD50 of homologous H5N1 challenge even when the challenge was administrated at 60 days post the boost.Conclusions/SignificanceThese results provide strong support for clinical evaluation of heterologous DNA-VLP prime-boost strategy as a public health intervention against a possible H5N1 pandemic.
Highlights
In the past century, three influenza pandemics have caused significant human fatalities throughout the world
The co-migration of H5HA and N1NA with HIV-1 gag in the sucrose density gradient indicates that both H5HA and N1NA are incorporated into virus-like particle (VLP)
Vaccination is the most economically prudent public health intervention strategy against both seasonal and pandemic influenza, to date, clinical evaluation of H5N1 vaccine candidates indicate the need for alternative approaches that could enhance vaccine immunogenicity and better protection
Summary
Three influenza pandemics have caused significant human fatalities throughout the world. Since 1997, highly pathogenic avian influenza (HPAI) H5N1 viruses have been spreading to numerous countries in Asia, Europe and Africa and infecting a large number of poultry and an increasing number of humans, often with lethal effects [1,2,3]. HPAI H5N1 transmission was found mostly via avian to human, continuous adaptation and/or re-assortment of HPAI H5N1 viruses may result in new strains capable of efficient human to human transmission. As a result, these viruses could cause significant morbidity and mortality, since humans are immunologically naıve to HPAI H5N1 viruses. DNA plasmid and virus-like particle (VLP) vaccines have been individually tested against highly pathogenic avian influenza (HPAI) H5N1 viruses, the combination of both vaccines into a heterologous prime-boost strategy against HPAI H5N1 viruses has not been reported before
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