Published on 16 December 2024

Evaluation of a novel vaccination strategy against influenza in the pig model

Combining an intramuscular vector vaccine with an intranasal live-attenuated influenza virus offers more advantages than simply immunising with the live-attenuated vaccine.

Significance of the study

Live-attenuated influenza vaccines (LAIVs) offer many advantages over the commonly used inactivated influenza vaccines. For example, they are able to induce a mucosal immune response that can prevent infection of the respiratory tract by virulent influenza viruses early in the chain of infection. However, it is not always easy to strike an optimal balance between satisfactory attenuation of the live vaccine and its immunogenicity. In an article now published in PLOS Pathogens, researchers from the IVI and the University of Bern show that both the safety of a live-attenuated vaccine and the induced immune response can be enhanced by a novel prime/boost strategy. The article impressively demonstrates that pigs immunised in this way develop sterilising immunity against infection with homologous influenza virus. This new vaccination strategy is therefore a promising approach for improved control of influenza outbreaks in humans and animals.

• Description of the study

  In a previous study at the IVI, a novel live-attenuated influenza virus was developed based on the 2009 pandemic H1N1 virus; the novel virus was characterised by a truncated NS1 protein and the absence of the accessory PA-X protein. Named NS1(1-126)-ΔPAX, the virus showed weaker replication in cell cultures and elicited a strong innate immune response (Avanthay et al., 2023, Front. Cell. Infect. Microbiol.13:1222805). The present study evaluated the efficacy of this vaccine candidate in pigs, as an animal model with relevance for influenza viruses. Nasal immunisation of pigs with the live NS1(1-126)-ΔPAX vaccine did not induce disease and elicited a strong mucosal immune response that completely blocked replication of virulent H1N1 in the respiratory tract. Surprisingly, the vaccine candidate replicated relatively well in the upper respiratory tract and was shed by the animals over a prolonged period of time. A novel prime/boost vaccination strategy was therefore developed in order to improve vaccine safety. First the animals were immunised via the intramuscular route with a non-replicating vesicular stomatitis virus (VSV) coding for the HA antigen of the pandemic H1N1 virus. Four weeks later, they were immunised with the live-attenuated vaccine candidate via the nasal route; after a further four weeks they were infected with the 2009 pandemic H1N1. Over the course of the study, the researchers investigated the effect of vaccine administration on the synthesis of influenza-specific antibodies in serum and mucous membranes, as well as the induction of influenza-specific T-cells. They also studied virus shedding using RT-qPCR analysis of nasal swab samples and investigated viral load post mortem in bronchoalveolar fluid and lung tissue. Finally, the lungs were examined for pathological lesions at the Veterinary Pathology Department of the University of Bern.

• What are the key findings?

  • Intranasal administration of the live vaccine NS1(1-126)-ΔPAX in pigs induces a strong local immune response that completely inhibits replication of virulent H1N1 in the respiratory tract.
  • Despite its attenuation, the live vaccine NS1(1-126)-ΔPAX is able to replicate in the upper respiratory tract to an extent that allows transmission to other individuals.
  • The novel prime/boost vaccination strategy significantly reduces shedding of the live-attenuated vaccine.
  • The new immunisation approach reduces the local immune response, although the latter is still sufficient to induce sterilising immunity.
  • The two-step immunisation procedure results in higher blood levels of influenza-specific antibodies, virus-neutralising antibodies and Th1 memory cells.

• What next?

  This promising new vaccination strategy is to be developed further. Three main questions will be addressed:

  • Does the immune response induced by the prime/boost protocol also protect against virus variants characterised by marked antigenic drift?
  • Does the new method induce longer-lasting protective immunity than conventional influenza vaccines?
  • Is shedding of the vaccine virus already sufficiently reduced to rule out virus transmission to naive animals?

Date July 2024

Title
«Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model»

Authors
Robin Avanthay, Obdulio Garcia-Nicolas, Nicolas Ruggli, Llorenç Grau Roma, Ester Párraga-Ros, Artur Summerfield, Gert Zimmer

Link
PLOS Pathogens Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model