Abstract
Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains.IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.
Highlights
IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines
In order to generate a California/04/09 H1N1 virus (Cal/09) Len live attenuated influenza vaccines (LAIVs) (Cal/09 Len), we introduced the following four residues previously identified as conferring the ts phenotype in the licensed Len master donor virus (MDV) into the rescue plasmids of Cal/09: PB2 I478L, PB1 K265N and V591I, and NS2 M100I (Fig. 1B) [29]
At 37°C, Cal/09 WT reached high viral titers similar to those obtained at 33°C, while the three LAIV viruses [Cal/09 Len, Cal/09 Len (PR8), and Cal/09 AA] achieved lower viral titers than at 33°C
Summary
IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. The live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. The last influenza season alone saw over 700,000 hospitalizations and more than 80,000 deaths [3, 4] Both an inactivated influenza vaccine (IIV) and a live attenuated influenza vaccine (LAIV). Seasonal formulations for both IIVs and LAIVs are developed each year to contain the surface antigens, hemagglutinin (HA) and neuraminidase (NA), of the predicted predominantly circulating strains of IAV [6] (Fig. 1A). Resident memory CD8 T cells (TRM) have been shown to underlie heterosubtypic immunity (i.e., antibody-independent immunity to a novel influenza virus, in mice previously infected with a different strain of influenza [11–13]). Recent studies have demonstrated that repeated antigen exposure extends the durability of lung CD8 TRM cells and that CD8 TRM cells in the upper respiratory tract greatly exceed the longevity of lung CD8 TRM cells and are independently capable of preventing pulmonary influenza infection [15, 16]
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