image: Intramuscular prime/intranasal boost vaccination protocol reduces LAIV shedding. (A) Schematic representation of the experimental design. Red points on the timeline indicate the time points of blood sampling. (B-D) Detection of viral RNA copies in nasal swab samples collected after intranasal inoculation of the animals with the indicated LAIV. At day 55 all animals were challenged via the nasal route using 106 ffu of pH1N1/09. Individual animals are represented by dashed lines and group mean values by continuous thick lines. (B) Pigs were first immunized (i.m.) with the VSV-Luc control vaccine followed by intranasal immunisation with NS1(1–126)-ΔPAX LAIV. (C) Pigs were immunized (i.m.) with VSV-H1 and subsequently boosted (i.n.) with NS1(1–126)-ΔPAX LAIV. (D) Animals were primed (i.m.) with VSV-H1 and boosted (i.n.) with NS1(1–126) LAIV. (E) AUC analyses of viral RNA load in nasal swab samples collected between days 0 and 17 after intranasal vaccination with LAIV (calculated with data from B-D). Significant differences of the AUC values were determined with the one-way ANOVA test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). Fig 2A was created with Biorender.com.
Credit: Avanthay et al, 2024, PLOS Pathogens, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)
A new, two-step flu vaccination strategy that pairs intramuscular injection of a viral vectored flu vaccine with nasal spray administration of a novel attenuated live flu virus appears to be safe and effective in pigs. Robin Avanthay of the Institute of Virology and Immunology in Mittelhäusern, Switzerland, and colleagues present these findings in the open-access journal PLOS Pathogens.
Seasonal flu vaccines typically consist of inactivated components of flu virus injected into muscle, helping the body’s immune system to recognize and fight the disease. However, this approach has limited ability to prevent infection where it initially occurs in the upper respiratory tract, and it can foster evolution of new versions of flu capable of evading immune attack.
An effective alternative is a live-attenuated vaccine, which uses a modified flu virus that has been weakened so it cannot cause disease. Live-attenuated influenza vaccines can be administered through the nose directly into the upper respiratory tract, where it prompts a multi-pronged immune response against infection. The authors’ novel live-attenuated vaccine candidate induced a strong local immune response that protected pigs against flu virus. However, although the vaccine did not cause any symptoms in pigs, it was shed from the upper respiratory tract for a prolonged time. If such a vaccine were used in humans, there is a chance that it could be transmitted to someone with a compromised immune system, potentially causing health problems.
Aiming to strike a balance between advantages and risks, Avanthay and colleagues developed a two-step immunization strategy. Prior to the nasal administration of the live-attenuated flu vaccine candidate called NS1(1-126)-ΔPAX, the animals were primed with a vesicular stomatitis virus (VSV) as a vaccine delivery mechanism. VSV represents a promising vector approach across vaccine research. However, in contrast to commonly used VSV-vectored vaccines, the vaccine used in this study was “propagation-defective”—engineered to perform only a single round of infection for safety.
When tested in pigs, this strategy resulted in a strong immune response, both body-wide and specifically in the upper respiratory tract where initial flu infection occurs. No infection was detected in the two-step-vaccinated pigs after they were exposed to virulent flu virus. Thus, as the novel immunization approach efficiently blocks flu virus replication in the upper respiratory tract, it may prevent shedding and transmission of flu virus during seasonal epidemics.
When compared to pigs that only received NS1(1-126)-ΔPAX on its own, the two-step-vaccinated pigs showed significantly less shedding of the vaccine candidate from their upper respiratory tract. Importantly, the intranasally administered live vaccine boosted the systemic Flu-specific antibody response and resulted in higher frequencies of Flu-specific T helper memory cells, which was the case if the live vaccine was used without prior priming. Thus, this novel two-step vaccination strategy may foster the duration of protective immunity as well as the protection against flu virus variants.
The researchers conclude that this novel two-step approach holds promise as a next-generation strategy for fighting flu more effectively, though further testing is needed before this vaccine approach can be used in humans.
Co-author Dr. Gert Zimmer summarizes: “A novel prime/boost vaccination strategy against influenza was evaluated in the porcine animal model. We combined the primary intramuscular immunization with a propagation-defective replicon vaccine with the secondary intranasal immunization using a genetically modified live-attenuated influenza vaccine (LAIV), and found that this immunization regimen resulted in reduced LAIV shedding, increased production of specific serum IgG, neutralizing antibodies, Th1 memory cells, and fully protected the animals against homologous virus challenge.”
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In your coverage, please use this URL to provide access to the freely available article in PLOS Pathogens: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012393
Citation: Avanthay R, Garcia-Nicolas O, Ruggli N, Grau-Roma L, Párraga-Ros E, Summerfield A, et al. (2024) Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model. PLoS Pathog 20(8): e1012393. https://doi.org/10.1371/journal.ppat.1012393
Author Countries: Spain, Switzerland
Funding: This work has received funding from the Swiss National Science Foundation (SNSF), grant no. 189903 (A.S., G.Z.; https://data.snf.ch/grants/grant/189903). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Journal
PLoS Pathogens
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model
Article Publication Date
8-Aug-2024
COI Statement
RA, GZ, and AS filed a patent related to the intramuscular prime/intranasal boost vaccine described in this work. All other authors declare no competing interests.