Image: ShutterstockInfluenza is a zoonotic disease, circulating through multiple animal species, which leads to events where different virus strains mix or swap their genetic material with one another, creating viruses never seen before. Influenza, like any virus, is also good at mutating itself away from protective immune responses and anti-viral drugs. As such, a vaccine or anti-viral drug that might be effective against a given version of an influenza strain, might not be effective against the mutated version.

Despite their limitations, seasonal vaccines are an essential countermeasure and have saved many lives. And there are several methods to produce influenza vaccines. In these methods, multiple strains are produced and mixed into a single vaccine. This provokes an immune response in a safe manner, without causing disease.

New versions of vaccines, or subunit vaccines, use one viral protein to elicit an immune response. All cases require careful monitoring of circulating strains for inclusion in the vaccine formulation. And while this analysis tends to lead to successful vaccines by selecting vaccine strains that align with the prevalent strains circulating in a particular season, there can be a mismatch. A mismatch can result in less effective protection for that given season (like in 2013 and 2014).

A universal idea
Development of a universal vaccine for influenza is an important endeavor. It holds substantial benefits, especially as strains continue to mutate.

The influenza virus infection is one of the most common infectious diseases globally, with the National Institutes of Health (NIH) noting about 3 to 5 million cases of severe influenza each year, with 500,000 deaths. According to the NIH, about 5 to 20% of the U.S. population fall ill to the influenza virus infection each year. In the U.S. more than 200,000 people are hospitalized, and 36,000 die, annually due to infection.

Should a universal vaccine come to fruition, it would likely provide protection to a greater proportion of the world’s population, stunting the effect of seasonal influenza and lowering the hospitalization and death counts. Essentially, a universal vaccine could protect people from new virus strains that emerge from genetic swapping and, thus, protect against potential pandemic strains.

Currently, there are several ongoing efforts to develop a universal vaccine for influenza, all in early stages of R&D. Many of these candidates hold promise. However, achieving a universal vaccine solution is challenging due to the virus’ variability and the variability of an individual’s immune response to the virus. This is further complicated in certain populations that don’t generate an effective response to vaccination, especially the elderly and immunocompromised. Within this segment, additional protective measures must be taken into account.

The importance of monoclonal antibodies
Monoclonal antibodies for influenza represent an important advancement to vaccinations and anti-viral drugs. These antibodies have been shown to reduce viral titers, which is critical for acute infectious diseases where time is of the essence. Compared to small-molecule drugs, antibodies can be given at sufficient concentrations to reduce the high viral concentrations seen in acute infections (like influenza).

Vaccination can be thought of as a way to get the body to produce antibodies. By identifying the epitome and engineering an antibody that provides universal coverage, this provides useful information in the efforts to develop universal vaccination strategies.

To help prevent influenza, Visterra has developed a monoclonal antibody, VIS410, which has the potential benefits in two situations. First, the company is developing VIS410 as a single administration for the treatment of hospitalized patients with influenza A infection, including seasonal and potential pandemic strains. “Anecdotal evidence suggests administration of an antibody or antibodies to severely infected patients, even several days after hospitalization, can help resolve disease faster and prevent many of the complications,” says a spokesperson from Visterra in an interview with R&D Magazine.

Second, since preclinical data demonstrate VIS410 targets an epitope that is universally present across influenza A strains, Visterra believes an antibody that targets this epitope may be administered prophylactically to individuals at high risk for infection in the event of an epidemic or pandemic. “In addition, we are working on a longer-lasting version of the antibody that we hope could be given once at the beginning of the influenza season and provide season-long protection,” says Visterra.

Visterra’s technology offers a new approach to address the challenges of infectious organisms and their ability to evade host immunological responses or resist treatment by currently available therapies. The antibody was developed using Visterra’s Hierotope technology platform to identify the ideal epitope on influenza hemagglutinin (HA), which enabled Visterra to design and engineer an antibody to target the specific epitope.

“Many studies have identified antibodies targeting HA on the virus surface have the strongest ability to neutralize the virus and provide enduring protections,” says Visterra. “Unfortunately, natural antibodies typically target sites on HA that are species-specific and can readily mutate.”

Using Visterra’s platform, the company identified an epitope on HA that was conserved across influenza A. And structural analysis of this epitope identified it was critical for the activity of HA, “such that it’s very difficult for the virus to mutate this site to avoid an antibody,” says Visterra. Since humans don’t typically make an antibody to this site, VIS410 was designed and engineered to precisely target this site.

“This involved multiple iterations between computational analysis and analysis of experiments conducted in the wet lab,” says Visterra. “In the end, we demonstrated in preclinical studies that VIS410 was able to bind to the targeted epitope and effectively bind and neutralize multiple strains of the influenza virus. The recent paper published in the Proceedings of the National Academy of Sciences (PNAS) demonstrated that VIS410 worked against H7N9. At the time VIS410 was designed, the H7N9 strains didn’t exist. By neutralizing the H7N9 virus, we demonstrated that this epitope is conserved even in mutated virus strains that occur through genetic swapping.”

The future
With influenza being the most common infectious disease globally, Visterra’s VIS410 provides hope as a further countermeasure for influenza, including emerging strains, such as the recently emerged H7N9 strains, which have been shown to cause pneumonia with acute respiratory distress syndrome and a high mortality rate. As the VIS410 targets a unique, conserved epitope on influenza A, Visterra is developing it currently as a single administration for the treatment of hospitalized patients with influenza A infection, including seasonal and potential pandemic strains.

The company has completed a Phase 1 clinical trial of VIS410, where they demonstrated the antibody was generally safe and well-tolerated. The company is currently in the process of completing a placebo-controlled Phase 2 challenge trial of VIS410 in healthy subjects that are administered an influenza virus in advance of receiving either VIS410 or placebo. 

Visterra anticipates completing this study by the end of the year and reporting the results shortly after study completion.

“We hope to soon study this antibody in patients suffering from severe influenza,” says Visterra. “Furthermore, we will continue to explore ways to increase the half-life of our antibody to provide season-long protection with a single injection.”


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