Article written by Pamuk Bilsel and Paul Radspinner, featured in Drug Discovery and Development February 7, 2023
For many years, vaccine developers have known that several problems with current influenza vaccines – short-lived serum antibodies, lack of immunity at the site of infection, and lack of robust protection against drifted strains – contribute to their modest efficacy. Although new approaches to influenza vaccine design, manufacture and administration have been explored, none has yielded an approved vaccine that addresses all of these problems.
mRNA COVID-19 vaccines have saved millions of lives worldwide since their approval, and their importance in combatting the pandemic cannot be overemphasized. However, these vaccines are already facing the same problems as influenza vaccines. Because they protect against illness but not infection, vaccinated individuals who contract the SARS-CoV-2 virus can still shed and transmit it.
To better control both viruses and the illnesses they cause, shifts in vaccine strategies are happening on two fronts: vaccine developers are beginning to recognize intranasal vaccines as key to inducing the local immunity that can block infection by a respiratory virus. Additionally, they are exploring combinations of influenza and COVID-19 vaccines that could offer a single solution to the infections.
FluGen is pursuing both strategies with its M2SR (M2 Deleted Single Replication) technology, which is based on a live but replication-deficient influenza virus delivered as an intranasal spray. M2SR was initially developed to improve influenza vaccine efficacy, and FluGen continues to work in that direction. But we are also using M2SR as a vector platform to develop a combination vaccine that addresses the problems faced by approved vaccines for influenza and COVID-19 alike.
Before delving into the design and initial results for FluGen’s combination vaccine, a brief description of M2SR itself is in order.
How M2SR technology works in influenza
M2SR is a live influenza virus in which M2, a protein the virus requires for replication, has been genetically deleted. The M2 protein is added back during manufacturing to produce a virus that cannot replicate more than once. The resulting vaccine is delivered as an intranasal spray.
Like inactivated or recombinant influenza vaccines given by intramuscular injection, M2SR stimulates immune responses to influenza A hemagglutinin (HA), a viral surface protein required for cell entry. But because it is a live, intact virus, M2SR also stimulates immune responses to neuraminidase (NA), nucleoprotein (NP), M1 and other conserved viral antigens – something inactivated and recombinant vaccines cannot do.
In addition to serum antibodies, the intranasal delivery of M2SR stimulates durable local immunity at the site of infection – the nose and upper respiratory tract – in the form of mucosal antibodies and cellular (T cell) immunity., Because it is replication-deficient, M2SR does not lead to any viral shedding or sequelae associated with intranasal vaccines based on live, attenuated viruses.
M2SR also elicits cross-reactive serum antibodies, meaning it remains efficacious even when the infecting strain of virus does not exactly match the strain used to make the vaccine – a phenomenon known as “viral drift.” M2SR has also demonstrated an excellent safety and tolerability profile to date, even with a dosing window 10- to 100-fold higher than for other intranasal vaccines.
These features enable M2SR to overcome the problems contributing to the modest efficacy of available influenza vaccines, which is 50-60% at best and can be less than 20% when the mismatch due to viral drift is high, as occurred in the 2014-2015 flu season.
FluGen has recently completed dosing and monitoring of subjects in a Phase 1b trial that is evaluating the safety and immunogenicity of an M2SR vaccine based on the H3N2 component subtype of influenza A (H3N2 M2SR) in combination with an approved influenza vaccine, compared with either vaccine alone, in older adults.
An M2SR combination vaccine for influenza and COVID-19
Many combination vaccines in development either combine the components of individual influenza and COVID-19 vaccines or deliver mRNA from both viruses. FluGen has taken a different approach by inserting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein into the DNA plasmids encoding the M2SR genome. By using M2SR as a vector to deliver a SARS-CoV-2 antigen, our bivalent COVID/Influenza M2SR vaccine provides immune protection against both viruses.
In mice, an M2SR-vectored bivalent vaccine based on the H3N2 virus and encoding the RBD from the original SARS-CoV-2 Wuhan strain elicited robust production of neutralizing antibodies against both Wuhan and the Delta variant while maintaining identical serum titers of hemagglutinin-inhibiting (HAI) antibodies and local immune responses to influenza as the M2SR H3N2 vaccine alone. Additionally, the bivalent vaccine generated mucosal IgA and IgG antibodies against Wuhan and variant Omicron strains without impeding the influenza responses.
FluGen is currently analyzing data from a study of the bivalent COVID/Influenza vaccine in hamsters challenged with SARS-CoV-2 and is continuing other preclinical studies of the bivalent vaccine, with plans to take the H3N2 version forward into clinical testing.
Planning for the future
Initially, our M2SR-vectored bivalent COVID/Influenza vaccine could be used alone or as an add-on to existing influenza or COVID-19 vaccines to provide broader and more durable protection against infection by influenza and SARS-CoV-2 viruses. Longer term, FluGen envisions developing a quadrivalent M2SR-vectored COVID/Influenza vaccine, in which each of the four vaccine components delivers an RBD from a different SARS-CoV-2 variant or different conserved epitopes from the viral spike protein that also elicit antibodies.
This combination vaccination strategy could offer the biopharma industry and consumers worldwide a single, elegant solution to the efficacy, durability and drift problems of current influenza and COVID-19 vaccines. In addition, this strategy could also reduce or eliminate the need to predict which influenza strains will circulate during flu season or play “vaccine catch-up” as new SARS-CoV-2 variants of concern emerge.
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Pamuk Bilsel, Ph.D., is the chief scientific officer of FluGen and Paul Radspinner, MBA, is the founder, president and CEO of the company.