In a study headed by researchers at the Institute of Virology and Immunology (IVI) in Mittelhäusern, 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. The scientists, led by Robin Avanthay, PhD, and Gert Zimmer, PhD, suggested that with further testing the novel two-step approach could hold promise as a next-generation strategy for fighting flu more effectively. The vaccine strategy, they commented, may be easily adapted to emerging influenza A virus (IAV) subtypes, with potential to help control future IAV pandemics.
The IVI scientists, working in collaboration with researchers at the University of Bern, and the University of Murcia, described the study and findings in PLOS Pathogens, in a paper titled “Evaluation of a novel intramuscular prime/intranasal boost vaccination strategy against influenza in the pig model.” In their report the team concluded “… our innovative vaccination regimen represents a promising strategy to control influenza disease and virus spread in both humans and livestock.”
Influenza A virus causes acute respiratory infections that in humans are usually associated with sudden high fever, muscle pain, headache, coughing, and fatigue lasting up to a week or more, the authors wrote. For some individuals the infection can be severe, or even life-threatening, particularly if the virus spreads to the lower respiratory tract, which can lead to viral pneumonia and acute respiratory distress syndrome (ARDS). Individuals most at risk include the very young, the elderly, and those with underlying diseases.
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. “The most commonly used human influenza vaccines to control seasonal epidemics are inactivated influenza vaccines standardized for hemagglutinin (HA) content,” the authors explained. Such vaccines trigger production of serum antibodies, but this approach has limited ability to prevent infection where it initially occurs in the upper respiratory tract, the team pointed out. “A small proportion of these virus-specific serum IgG is secreted into the lower respiratory tract where they protect against severe influenza pneumonia and ARDS … However, secretion of serum IgG into the mucosal tissues of the upper respiratory tract is not efficient.” Such vaccines might also foster evolution of versions of flu capable of evading immune attack.
An effective alternative is a live-attenuated influenza vaccine (LAIV) 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, prompting a multi-pronged immune response against infection. “Live-attenuated influenza vaccines (LAIV) offer several advantages over inactivated influenza vaccines because they are administered via the natural route of infection and induce a local immune response directed against multiple viral antigens,” the investigators added.
For their newly reported study the team evaluated their novel live-attenuated vaccine candidate, NS1(1–126)-ΔPAX, in pigs, demonstrating that the vaccine induced a strong local immune response that protected animals 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.
“To improve LAIV safety, we developed a novel prime/boost vaccination strategy combining primary intramuscular immunization with a haemagglutinin-encoding propagation-defective vesicular stomatitis virus (VSV) replicon, followed by a secondary immunization with the NS1(1–126)-ΔPAX LAIV via the nasal route,” the researchers wrote. “The selection of the VSV vector was based on our previous work demonstrating an efficient induction of antibody and T cell responses to the HA antigen that mediated partial protection of pigs against heterologous IAV challenge.”
When tested in pigs this two-step vaccination 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.
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. The collective results, the investigators stated, “… demonstrate that our novel intramuscular prime/intranasal boost vaccination protocol induces enhanced systemic IAV-specific immunity in terms of higher IgG, higher neutralizing antibodies titers and enhanced memory Th1 cells. These systemic responses combined with the induction of local mucosal immunity in the respiratory tract provided sterilizing immunity against homologous virus infection.”
Importantly, when compared with 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. “… the combination of the intramuscular immunization with VSV-H1 and the intranasal boost using the NS1(1–126)-ΔPAX LAIV enhanced the safety by strongly reducing LAIV shedding and completely preventing shedding of challenge virus,” the scientists reported.
Summarizing the team’s study and findings, Zimmer said, “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.”
This novel two-step vaccination strategy may foster the duration of protective immunity as well as protection against flu virus variants, they suggested. “It will be of high interest to analyze in future experiments whether our prime/boost vaccination regimen and the induction of a strong memory T cell response will also provide protection against antigen-drifted IAV.”
The authors further concluded, “… the present novel prime/boost vaccination protocol provides a basis for the development of alternative next-generation vaccination strategies that will help to more effectively control seasonal influenza epidemics and persistent circulation of IAV in livestock. In particular, the mucosal immunity induced by this vaccine strategy may reduce the spread of IAV and help to improve the level of herd immunity. As this prime/boost vaccination strategy can be easily and timely adapted to emerging IAV subtypes, it may also be useful in the control of future IAV pandemics.”
