Need to know:
- In places where Covid-19 vaccines are readily available, many people who want to be vaccinated have already received their first two doses and even a booster. Manufacturers are now looking for ways to improve their vaccines.
- One way is by having a vaccine that is protective against Covid-19 and the flu. Although available data so far support the potential for positive efficacy and safety, it needs to be clarified how such a vaccine should be distributed.
- Companies are also looking to have variant-specific or multivariate vaccines. However, experts took issue with this approach because the original vaccine is still effective against newer variants, and so such an adjustment may not be necessary. However, there is scientific value of these studies in case of another pandemic risk by another similar virus.
Moderna and Novavax’s Covid-19 and influenza combination vaccine attracts expert enthusiasm for efficacy due to the former’s mRNA vaccine technology and the latter’s non-inferior data for its independent protein subunit influenza vaccine. They were less enthusiastic about Moderna and Pfizer / BioNTech’s study of variant-specific or multivariate Covid-19 vaccines, and noted the fog had commercial or practical value despite the scientific significance of the studies.
As for the Covid-19 / influenza vaccines, the assets with two antigens should not interfere with each other’s efficacy when combined and their adverse reaction profiles should correspond to independent versions. The one notable caveat with this approach is that although influenza has a predictable annual seasonal variation, the same cannot be said so far with Covid-19, which may make it difficult to designate ideal distribution timelines for the combination. Novavaxs Phase I / II combination vaccine survey (NCT04961541) has data expected in April, while Modernity is still in the preclinical phase.
Regarding variant-specific or multivariate Covid-19 mRNA vaccines, the lack of expert enthusiasm is due to data from the current crop of vaccines showing that they are still effective against newer variants of concern. By the time a vaccine is adapted to contain the latest variant, there is a risk that the variant will no longer be widespread in society. Nevertheless, there is scientific justification for these studies to show that existing vaccine technologies can be adapted to future variants.
Modern variant-specific vaccines are targeted at Beta, Delta or Omicron and the multivariate shot reset on both Beta and Delta in a Phase II / III trial (NCT04927065). Pfizer / BioNTech targets Phase II Alpha / Delta (NCT05004181). The Pfizer / BioNTech trial is expected to end in April, while Moderna’s trial is expected to end in March 2023.
Covid-19, the flu combo vaccine has benefits
A Covid-19 / influenza vaccine is attractive as it combines two preventative approaches into one, says Dr. William Schaffner, Professor of Infectious Diseases at Vanderbilt University. The combination can reduce vaccine hesitation and ease public fatigue over vaccinations, explains Rodney Rhode, PhD, president and professor, Clinical Laboratory Science Program at Texas State University.
Novavax’s combination vaccine with protein subunit has not yet been approved by the US Covid-19 vaccine Nuvaxovid and its Phase III seasonal influenza vaccine NanoFlu. Meanwhile, Moderna’s combination vaccine contains its FDA-approved Covid-19 vaccine Spikevax and its seasonal influenza vaccine mRNA-1010, with the most recent study of the latter independent vaccine being a Phase I / II trial (NCT04956575).
Superiority ideal for flu element
In order for these combination vaccines to strengthen their true value, experts say that their flu vaccine element should be improved over available stand-alone flu vaccines. Existing influenza vaccines typically offer 40-60% protection. The combination vaccine should have at least 60% protection for better uptake, Rhode says.
In a Phase III trial (NCT04120194), Novavax’s NanoFlu non-inferior immunogenicity relative to the active comparator Sanofis Fluzone quadrivalent vaccine. Although NanoFlu is only non-inferior, the added Covid-19 element to its combination will provide an additional selling point, Rhode explains. There are no concerns that the combined version will be less effective compared to the stand-alone influenza vaccine, as Novavax uses the same technology in influenza and its Covid-19 vaccines, he adds.
mRNA technology attracts enthusiasm
It is only recently did mRNA technology begin to be tested for influenza, and the shift is due to the success of Covid-19 mRNA vaccines, says Dr. Reynold Panettieri, Jr., Vice Chancellor, Rutgers Institute for Translational Medicine and Science. And mRNA technology has the potential to increase the effectiveness of existing flu vaccines, Rhode explains.
Moderna’s stand-alone mRNA-1010 influenza vaccine produced positive preliminary phase I data showing enhanced influenza antibody titers in participants 18 years of age and older. Preclinical data from Novavax show that its combination vaccine produced high levels of influenza haemagglutination inhibitory (HAI) antibody response to a viral infection, neutralizing antibodies to influenza A and B strains and maintaining protection against SARS-CoV-2.
Yet such positive preclinical data do not guarantee the same results in human trials, Rhode says. The human immune system responds differently to dosage, the drugs tested have different interference with human proteins and enzyme kinetics, as well as the effects of antibody response longevity compared to laboratory animals, he explains.
Unknown seasonal fluctuations
The two combinations should also demonstrate that the effectiveness of its Covid-19 vaccine element should not be compromised by the added flu vaccine, Panettieri says. Reduced efficiency when combined is a valid concern that would affect its marketability, Rhode explains. It is reassuring that there are no examples of less effective combination vaccines still being distributed to all independent counterparties, he notes.
The combination vaccines are likely to have similar side effects as stand-alone versions, such as soreness, muscle fatigue, fever and nausea, Rhode adds. So far, existing combination vaccines are as safe as stand-alone versions, Rhode and Panettieri note.
Nevertheless, if a combination vaccine is approved, there are rollout issues that need to be addressed. There is an established seasonal for influenza, and therefore it is updated every year with a predictable schedule, adds John McCauley, director of the Worldwide Influenza Center at the Francis Crick Institute.
Covid-19’s seasonal, while there is a tendency for winter peaks, is still foggy and there are still questions if people need to be given a Covid-19 vaccine annually to counteract the diminishing effect, or only when there is an aggressive new variant that has a significant impact on the vaccine’s effectiveness. “You have to be really strict and on top of your genomic monitoring. The world has to constantly look at these strains and new varieties,” says Rhode.
Value concerns about variant-specific vaccines
Meanwhile, efforts for variant-specific or multivariate Covid-19 mRNA vaccines are also underway. While the first crop of Covid-19 mRNA vaccines showed at least 90% efficacy against the original variant, it will be a challenge to approach this high level of efficacy at present due to vaccination rates in the community, immunity to previous infections as well as more aggressive variants. “Comparing past and present immunogenicity data is like comparing apples to oranges,” says Panettieri.
Nevertheless, there is tremendous practical and commercial value of these variant-specific or multivariate Covid-19 vaccines, given that the original vaccines are still robust to all variants, says Panettieri. “We have to be careful about trying to perfect something that is not broken,” he says. Boosters reduced morbidity and hospitalization of infected patients, he added. Three doses of original Pfizer and Moderna vaccines had 90% protection against serious illness caused by the Omicron variant, according to UK’s Health Security Agency.
Furthermore, when variant-specific or multivalent vaccines may be available on the market, the variants they are investigating against may no longer circulate, says a vaccine expert. “You will always chase your tail to some degree,” he adds.
Instead, greater efforts should be made to improve vaccine distribution instead of improving a vaccine that is still effective, says the vaccine expert. Moderna has announced to provide access to technology producing their Covid-19 vaccine to low- and middle-income countries, where BioNTech provides modular mRNA production facilities to improve vaccine supply in Africa.
Scientific justification present
Nevertheless, there is still scientific value in studying these variant-specific or multivalent vaccines, as they can be valuable if we need them in the future, says the vaccine expert. A Pfizer spokesman says being vigilant against the virus requires identifying new ways to protect yourself as SARS-CoV-2 develops naturally. Developing and exploring different approaches, should they be necessary, is crucial to their goals, she adds.
Moderna has said that previous research into SARS-CoV-1 and MERS enabled the company to respond quickly to the Covid-19 pandemic. Moderna and Novavax did not respond to a request for comment.
Moderna is only testing its vaccine as a booster, while Pfizer and BioNTech are also studying their vaccine in vaccine-naive people. While a significant number of people have received two doses, arguing for only examining these as boosters, there are many people who are still vaccine-naive, especially in places that are harder to reach, he added.
It is reassuring that variant-specific or multivariate vaccines are unlikely to pose a higher risk of side effects than the original version, says Schaffner. The side effects are attributed to the technology of the vaccine and not the antigen, he explains.