A major limitation of currently available influenza vaccines is their modest efficacy, which stems from several problems: their limited ability to block infection and prevent viral spread, the short duration of the immune responses they induce, and their ineffectiveness against drifted or “mismatched” strains of flu. To solve these problems, FluGen is developing its M2SR (M2 Deleted Single Replication) technology. M2SR is based on a live but replication-deficient influenza virus, delivered as an intranasal spray, that results in broader and more durable immune responses to influenza, especially at the site of infection, and greater efficacy in preventing infection and illness.
The technology also has potential utility in vaccine combinations. For example, M2SR vaccines could be combined with current influenza vaccines to offer broader protection to vulnerable populations, especially older adults; and the M2SR technology serves as a platform for the development of bivalent COVID/Influenza vaccines that address the limitations of approved COVID-19 vaccines.
Influenza vaccines: Room for improvement
Influenza vaccines fall into three broad categories: inactivated influenza vaccines (IIVs), recombinant influenza vaccines (RIVs) and live attenuated influenza vaccines (LAIVs).
IIVs deliver an inactivated virus that presents primarily influenza A hemagglutinin (HA), a surface protein the virus requires for cell entry, to the immune system. RIVs deliver purified, recombinant HA antigen instead of a virus-derived antigen. Because they are administered via intramuscular injection, both IIVs and RIVs elicit high serum titers of hemagglutinin-inhibiting (HAI) antibodies. However, they do not elicit antibodies against other important viral antigens, such as neuraminidase (NA) or nucleoprotein (NP), which limits their efficacy to, at best, 50-60%. Serum HAI antibodies also provide no local immunity at the site of infection – the nose and upper respiratory tract – which means IIVs and RIVs cannot prevent influenza infection; they can only prevent or minimize the illness arising from the infection.
LAIVs contain a live but weakened virus delivered as an intranasal spray. Unlike the other two vaccine types, LAIVs may stimulate local immunity, but they depend on viral replication to generate protective immunity. This dependence limits their efficacies in individuals with pre-existing influenza immunity that prevents vaccine virus replication.
The efficacies of all three vaccine types can be adversely affected by viral drift, which is the tendency for the influenza virus to accumulate changes in the HA and NA surface antigens over time. When drift occurs, antibodies elicited against one strain of virus eventually fail to recognize and neutralize newer, “drifted” versions of the virus. Viral drift can also result in mismatches between the selection of the viral strain(s) used to manufacture the annual vaccine and the strains that actually circulate during flu season. When the mismatch is high, vaccine efficacy can be quite low, as was the case during the 2014-2015 flu season, when overall efficacy of the vaccine was less than 20%,
Furthermore, current influenza vaccines provide only a few months of protection, which is shorter than the annual flu season; and because they do not protect against infection, vaccinated individuals can still contract the virus, shed it, and transmit it to others, even if they experience no overt symptoms of infection.
M2SR: Solving the problems of influenza vaccines
FluGen’s M2SR vaccine technology addresses all of these issues. 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, producing a virus that can only replicate one time. The resulting vaccine is delivered as an intranasal spray.
Unlike IIVs and RIVs, M2SR mobilizes the entire immune system by stimulating immunological responses to HA as well as NA, NP and other conserved viral antigens, and by stimulating durable local immunity at the site of infection in the form of mucosal antibodies, serum antibodies and cellular (T cell) immunity., Additionally, because it can only replicate once in the vaccinated individual, M2SR does not lead to the viral shedding or sequelae associated with LAIVs based on replication-competent viruses.
M2SR also elicits cross-reactive responses that address viral drift, meaning it remains efficacious even when the infecting strain of the virus does not exactly match the strain used to make the vaccine. For example, in a Phase 2 challenge study, an M2SR vaccine based on a 2007 strain of the H3N2 subtype of influenza A – dubbed H3N2 M2SR – protected vaccinated subjects against subsequent challenge with a highly drifted H3N2 strain from 2015.
M2SR has also demonstrated an excellent safety and tolerability profile, even with a dosing window 10- to 100-fold higher than for other intranasal vaccines – again, because M2SR replicates only once.
FluGen has developed all four components needed for a quadrivalent M2SR influenza vaccine. However, initial clinical testing has focused on the H3N2 M2SR component because H3N2 causes the most serious illness, especially in older adults, and current vaccines typically have the lowest efficacy against it.
Vaccine combinations for influenza – and more
To protect older adults against influenza, FluGen is exploring the possibility that combining the H3N2 M2SR vaccine with an approved influenza vaccine will offer the best of both worlds: the local, durable immunity of M2SR; and the high titers of serum HAI antibodies elicited by injected vaccines that are essential to protecting this vulnerable population.
FluGen is conducting a clinical trial, funded by the US Department of Defense, to evaluate the safety and immunogenicity of H3N2 M2SR alone, Fluzone High Dose alone, and the combination of both vaccines in a total of 305 adults aged 65-85. Dosing and monitoring of the trial participants was completed in September 2022, with immunogenicity data expected in the first quarter of this year. To date, no severe adverse events have been reported.
M2SR technology is also being used by FluGen to develop a combined COVID/Influenza vaccine that could address the shortcomings of approved COVID-19 vaccines, which now face the same challenges as influenza vaccines: short-lasting serum immunity against a single antigen; lack of immune protection at the infection site; and lack of protection against drifted strains, most recently the Omicron variant of SARS-CoV-2.
FluGen’s approach involves inserting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein into the DNA plasmids encoding the M2SR genome, thus using M2SR as a vector to deliver a SARS-CoV-2 antigen. In preclinical mouse studies, an M2SR-vectored COVID/Influenza vaccine based on H3N2 and the RBD from the Wuhan strain of SARS-CoV-2 elicited robust immune responses to multiple SARS-CoV-2 variants, including Omicron, while maintaining identical serum and local immune responses to influenza as the H3N2 M2SR vaccine alone. Preclinical studies of the bivalent vaccine continue, and FluGen plans to take the H3N2 version into clinical testing.
This bivalent vaccine could be used initially, alone or in combination with other influenza and/or COVID-19 vaccines, to provide broader and more durable protection against infection by both viruses. Longer term, FluGen intends to develop a quadrivalent, M2SR-vectored COVID/Influenza vaccine, in which each of the four vaccine components delivers a different RBD or even different conserved epitopes from the viral spike protein.
There is still a pressing need worldwide for effective approaches to managing endemic and pandemic influenza and SARS-CoV-2 viruses. With its versatile M2SR technology, FluGen is excited to be at the forefront of innovation in vaccines and vaccine combinations that will better prevent disease and greatly reduce the morbidity and mortality associated with viral infections.
- Eiden J, Gordon G, Fierro C, et al. Vaccines (Basel). 2021;9(12):1388. doi: 10.3390/vaccines9121388.
- Eiden J, Fierro C, Schwartz H, et al. J Infect Dis.; published online Nov. 9, 2022. 10.1093/infdis/jiac433
- Eiden J, Volckaert B, Rudenko O, et al. J Infect Dis. 2022;226(1):83-90. doi: 10.1093/infdis/jiab374.
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