After Covid-19, mRNA technology aims to revolutionise the flu shot

The efficacy for messenger ribonucleic acid (mRNA) vaccines is highly pathogen-dependent, which means breakthrough success seen in Covid-19 may not necessarily translate to all infectious diseases, such as influenza.

There will be distinct factors driving efficacy compared to vaccines designed against SARS-CoV-2, including the need to target multiple viral antigens, and individual influenza virus-specific characteristics.

Nonetheless, mRNA vaccines provide a valuable time bump, even by a few weeks, which could be crucial in improving their ability over traditional shots to accurately target the dominant flu strain that year.

Pfizer and BioNTech’s Comirnaty (BNT162b2) and Moderna’s Spikevax (mRNA-1273) were not only the first mRNA-based vaccines to be authorised by the US Food and Drug Administration (FDA) for use against the SARS-CoV-2 virus, but also the most successful applications of the technology to date. 

While this set the stage for vaccine development in other infectious diseases, experts said overall efficacy for seasonal influenza depends on several factors like the nature of the main strain that year or the impact of prior exposure to the virus. Most individuals are expected to have some form of passive immunity if previously exposed to influenza, which can interfere with the activity of an mRNA flu vaccine, experts said.

Also, traditional seasonal flu vaccines target three or four influenza strains, while both the authorised mRNA Covid-19 vaccines specifically carry the code to translate part of a sequence or the entire spike protein on the SARS-CoV-2 virus.

By virtue of its design, the mRNA vaccine can be designed to include several mRNAs coding for multiple antigens, and this is significant in the case of influenza vaccines that need to provide protection against multiple strains.

Sanofi initiated a Phase I study with Translate Bio with their monovalent flu vaccine. While Translate Bio did not specifically comment on this story, it did confirm that Phase I study results will be available by the end of 2021.

In early August, Sanofi announced its plans to acquire Translate Bio and its mRNA technology platform. Others like Moderna use a multivalent approach, which experts say is necessary in the case of a seasonal influenza vaccine.

Moderna initiated its own Phase I/II study with its mRNA flu vaccine mRNA-1010 in July. Arcturus Therapeutics plans to file a Clinical Trial Application (CTA) to start a study for its LUNAR-FLU candidate with regulatory agencies this year.

Pfizer, BioNTech and Moderna did not respond to a request for comment, while Arcturus did not respond before deadline.

SARS-CoV-2 was relatively easy to neutralise and protect against, but current mRNA technology will likely not guarantee 90% or higher protection for all pathogens, said Dr Neil King, assistant professor at the University of Washington’s Institute for Protein Design.

The platform may not necessarily work as well for all antigens, agreed Children’s Hospital of Philadelphia Vaccine Education Center visiting research scientist Angela Shen. Both Comirnaty and Spikevax have been more than 90% effective in preventing SARS-CoV-2 infections in real-world studies.

While clinical data with Moderna’s seasonal flu candidate is awaited, the company has previously studied an mRNA vaccine targeting the influenza strains of H10N8 and H7N9 with pandemic potential.

Here, the immunogenicity profile was not outstanding, and while it induced neutralisation and haemagglutinin inhibition titers, it was not differentiated enough from traditional vaccines, said NIAID Vaccine Research Center chief of molecular immunoengineering Dr Masaru Kanekiyo.

At the highest doses, the intramuscular doses of the vaccine against H10N8 and H7N9 induced haemagglutinin titers of greater than or equal to 1:40 in 100% and 89.7% of participants, respectively.

An increase in antibody titers to haemagglutinin is said to correlate with protection from the viral infection. The titer reduced after six months, which could be a flu-specific phenomenon rather than related to the mRNA technology because this was not seen with the Covid-19 vaccine, said Kanekiyo. Hence, it is still unknown if mRNA technology will be a game-changer for flu vaccines specifically, he added.

Moreover, assessing vaccine efficacy is complicated, especially in influenza, said Dr Mark Sawyer, a voting member on the FDA Vaccine Advisory committee that authorised the Covid-19 mRNA vaccines.

If the mRNA vaccine has a substantial improvement in mortality over traditional vaccines, of say 15%-20%, then that may be favoured especially in high-risk groups, said Sawyer, who is also an infectious disease physician at Rady Children’s Hospital in San Diego. However, in lower-risk groups, only preventing illness is less significant, he added.

Traditionally, greater than 75% efficacy in preventing symptomatic infections is a major goal in the field, said Kanekiyo. Inactivated flu vaccines are associated with a 40%-70% efficacy, as per an analyst report. However, even that is a broad estimate since 70% efficacy has not been observed in approximately the last decade, said Sawyer.

In general, physicians desire higher efficacy with flu vaccines, especially such that it lasts throughout the season, said Tufts Children’s Hospital chief of paediatric infectious diseases Dr Cody Meissner.

The influenza virus also presents a different challenge compared to coronaviruses because very few people had immunity to the SARS-CoV-2 virus when they received a vaccine, said Dr Richard Webby, director of the World Health Organization (WHO) Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds at St Jude Children’s Research Hospital in Memphis.

In the case of Covid-19, the vaccines were directed to the viral spike protein that the immune system had likely not encountered before, he said.

An individual’s immune history can substantially affect the subsequent response to the vaccine, and this is different from targeting a pathogen-naïve population in the case of SARS-CoV-2, said King. Whether immunising people with existing antibodies to the protein that the vaccine is making interferes with or blunts the vaccine response remains to be seen, said Webby.

On the other hand, individuals who had prior Covid-19 infections have shown a high antibody response after vaccination, said Melbourne-based postdoctoral researcher Dr Emily Pilkington of the Pete Doherty Institute for Infection and Immunity.

Nonetheless, factors driving immune protection are very complex and they differ based on the individual virus, said Meissner. The role of cellular immunity in relation to humoral immunity providing protection against influenza is also not well understood, he added. This is likely to make the vaccine design more complex since it would affect antigen selection and the way it is presented, said King.

Traditional vaccines are grown in hen eggs and for the flu virus to adapt to growth in these eggs, mutations in the haemagglutinin and neuraminidase proteins – targeted by the vaccine – would make the virus a bit different from what humans will encounter, said Meissner. This will not be an issue with mRNA vaccines, said King.

Traditional flu vaccine development has followed a pathway wherein the WHO makes recommendations on the predominant viral strain in February and September for northern and southern hemispheres respectively.

It then takes at least six months to develop a vaccine against that specific strain. Given the propensity of the influenza virus to mutate, it is important to pick strains closer to the onset of the influenza season, said Meissner.

Mismatches between circulating strains and the ones the seasonal vaccine target can affect vaccine efficacy, said King. For example, in 2014, a strain emerged in March, but the selection was done in February, and there was a mismatch between the vaccine and the circulating strains, said Webby.

Sometimes even an extra two to three weeks of data can help identify the right circulating strain. So, if the strain selection decision can be made later due to the mRNA platform, that would represent an improvement over current vaccines, he added.

The flexibility in targeting multiple strains and the speed at which the development can go from sequence identification of the circulating strains to production will be a big benefit with mRNA vaccines, said University of Pennsylvania professor of medicine-infectious diseases Dr Harvey Friedman. Comparatively, making an inactivated vaccine takes longer even if it is simpler, he added. 

The shorter timelines to develop an mRNA vaccine are a significant advantage over traditional technology because they can reduce strain mismatch, said Kanekiyo. mRNA vaccines would take only a few days to clone the appropriate mRNA sequence and relatively shorter to incorporate that sequence into lipid nanoparticles for administration, said Meissner.

Influenza vaccines have traditionally had to be effective against three or four viral strains. The Covid-19 vaccines have specifically targeted the spike glycoprotein on the SARS-CoV-2 virus. The advantage of the mRNA platform is that theoretically multiple mRNA molecules of selected antigens can be used, said Webby.

This could mean mRNA vaccines target more haemagglutinin and neuraminidase proteins than traditional vaccines, and potentially even antigens encoding for other viruses, said Meissner.

Sanofi/Translate Bio’s candidate codes for the hemagglutinin protein of the A/H3N2 strain of the influenza virus. Moderna’s mRNA flu vaccine is quadrivalent targeting the A H1N1, H3N2 and influenza B Yamagata and Victoria lineages.