Why vaccination is important and the safest way to protect yourself

Combined COVID-flu Vaccines Are Coming: Moderna Jab Clears Major Test

Pharmaceutical laboratories are researching new applications for mRNA vaccine technology — and Moderna is hoping to integrate COVID-19, influenza and respiratory syncytial virus immunization into a single jab.Credit: Adam Glanzman/Bloomberg via Getty

A single vaccine has been shown to protect people from both SARS-CoV-2 and influenza viruses — and with a higher effectiveness than vaccines that target one or the other, the pharmaceutical company Moderna has announced.

Moderna, which is based in Cambridge, Massachusetts, said earlier this month that it had successfully completed phase-III clinical trials for the drug, which — like the company's pioneering COVID-19 vaccines — is based on mRNA. In a statement to its investors, Moderna said that the vaccine was more effective at providing immunity to adults over the age of 50 than competing flu and COVID-19 shots.

Moderna is now planning to seek approval from the US Food and Drug Administration (FDA) to bring the vaccine to market.

Combination vaccines can have big public-health benefits, but they are often time-consuming and expensive to develop. Moderna's latest rapid success shows that RNA can help to overcome some of these difficulties, says James Thaventhiran, a clinical immunologist at the University of Cambridge, UK, "This is a great example of why the technology is exciting," he says, adding that the combination vaccines using mRNA are "just the beginning" for RNA technology.

The RNA effect

Vaccination helps people to build immunity to a disease by exposing their immune cells to an antigen, such as a protein, a snippet of DNA or even a whole pathogenic organism that has been inactivated. When the real pathogen comes along, the immune system is quickly able to recognize the threat and mount a resistance.

Creating antigens is a difficult process, and combining different antigens into one vaccine increases its complexity further. "It sounds like it should be so easy, right? You just mix them together," says Jacqueline Miller, a paediatrician and head of development for infectious disease at Moderna. "But it's actually much more complicated than the development of individual components."

The chemical components that make up single-target vaccines can sometimes react with one another when combined, running the risk of making the individual drugs less effective. MRNA-based vaccines don't face as much of a hurdle, however, because the drug components for different antigens tend to be the same.

mRNA is a molecule made of nucleic acids, and its main purpose is to tell cells what proteins to make. MRNA-based vaccines inject mRNA into cells to make copies of antigens for the immune system to recognize. So, rather than having to make a bunch of different components, mRNA vaccines simply wrap up a set of instructions in a layer of lipids and then send them into the body for cells to pop out their own antigens.

The result is a strong immune reaction based on drug components that don't compete with one another — even if they are targeting different pathogens.

That might explain why the risk of combination vaccines being ineffective is "clearly" not a problem with the new COVID-influenza vaccine, says Thaventhiran, because the shot seems to boost immunity more than single immunizations do.

The vaccine's code can also be quickly changed to keep up with evolving variants. One of the issues with current, non-mRNA influenza vaccines is that the antigen is grown in chicken eggs, a process that takes six months. During that time, the virus can mutate and change. By contrast, "with RNA it literally takes weeks to make a new variant", says Drew Weissman, an immunologist at the Perelman School of Medicine University of Pennsylvania in Philadelphia.

Modern mRNA immunization

Researchers have been testing the limit for the number of antigen instructions they can fit into an mRNA vaccine; one group has fit mRNA instructions for all 20 variants of influenza into a lipid layer1. Moderna is hoping to add the respiratory syncytial virus (RSV) — which causes cold-like symptoms — as a third pathogen to its current COVID–influenza pair.

For most people, FDA approval of the Moderna shot "means one visit to the pharmacy", says Weissman. "One shot will be enough to protect you from both the flu and COVID."

COVID-19 booster uptake has dropped in the United States since the first rounds of vaccinations. However, as of this year, around 47% of adults have received the flu shot, according to the US Center for Disease Control. Combining immunizations could help to ensure that more people are protected from COVID-19, says Miller.

And looking forward, mRNA combination vaccines could help to reduce the burden of immunizations for parents of young children. Infants are currently the primary targets of available combination vaccines, but they are still given multiple rounds of shots in the first few years of their lives. "Parents would be ecstatic" to reduce the number of shots their children must get, says Weissman. And having just a few shots — which could be administered at the same time — would also help to ease that burden of immunization in rural communities in low-income countries.

Researchers will have to work out how to deal with the delicate nature of mRNA to see these benefits expand outside of high-income nations, says Thaventhiran. Part of the challenge of rolling out COVID-19 vaccines was the need to keep doses in deep freeze to protect the mRNA from breaking down.

But overall, the development of mRNA combination vaccines is evidence "that RNA has a positive future", says Weissman. "It isn't just a fluke."

Influenza Vaccine Market Dynamics

 'Rocky recycled chair' image courtesy of Nigels Eco Store.

The market for seasonal influenza vaccines, sized at US$2.8 billion in 2008–2009 across the seven major markets (United States, Japan, France, Germany, Italy, Spain and UK), has had a strong compound annual growth rate of 12.6% since 2005–2006 (Ref. 1). In recent years, the sector has benefited considerably from an increase in disease awareness and funding, triggered by the threat of an influenza pandemic. However, owing to increasing competition and market commoditization, maintaining this strong growth momentum will be a key challenge in the future. The cautious stance of regulators towards new technologies inhibits successful product differentiation, particularly in the crucial US market. Improved vaccines for the elderly, alongside faster and more flexible manufacturing technologies, are the key unmet needs.

The influenza vaccines market is a challenging sector for several reasons. Besides requiring annual updates, seasonal influenza vaccines have to be produced and shipped within a short time frame of 6 months. Manufacturing delays and reduced output can result in losses of revenue and market share. Additionally, the demand for seasonal influenza vaccines is variable and often unpredictable, being influenced by factors such as the weather, the timing and severity of the influenza season, vaccine availability and public awareness of vaccination. These factors make production planning difficult. The pandemic influenza vaccines business is even more unpredictable and depends almost exclusively on government stockpiling and supply contracts.

A re-emerging focus for vaccine players

Historically, the influenza vaccine landscape has undergone marked fluctuations, particularly in the United States. The country remains the single largest market for seasonal influenza vaccines, accounting for 40% of overall sales across the seven major markets in 2008–2009 (Ref. 1). In the 1970s, at least ten US firms were marketing seasonal influenza vaccines. As a consequence of stricter FDA regulations and poor returns on investment compared with other pharmaceutical sectors, only three companies remained in the market in 2002: Wyeth, Aventis Pasteur (now Sanofi Pasteur) and PowderJect (now Novartis). In 2003, Wyeth ceased production of its own vaccines to concentrate on marketing MedImmune's (now part of AstraZeneca) FluMist, but decided to leave the flu space altogether in 2004.

Two factors prompted a change in US policy: the emerging threat of a pandemic caused by the H5N1 avian influenza strain since 2004 and a perceived vaccine supply shortage in 2004–2005 following disruptions at Chiron's (previously PowderJect's) manufacturing facility. The US government subsequently began to invest heavily into establishing US-based influenza vaccine production capacity, aiming to decrease the country's dependence on vaccine imports from few, mostly European, manufacturers. Furthermore, the US provided an additional growth stimulus by sequentially expanding recommendations on seasonal influenza vaccination to include more than 85% of the country's population by 2009 (Ref. 2). This combination of 'push' and 'pull' incentives transformed the sector's commercial potential, attracting numerous vaccine developers to build and expand their influenza portfolios in the United States. Following the market entry of GlaxoSmithKline (GSK) in 2005 and CSL in 2007, the number of vaccine suppliers for the US market has increased to five in 2009, with Sanofi Pasteur as the market leader (Fig. 1).

Figure 1: Vaccine providers for the US market for the influenza seasons 2000/2001–2008/2009.

GSK, GlaxoSmithKline. Data from Refs 1, 5, 6, 7.

However, as the demand for seasonal influenza vaccination in the general population has failed to meet the expectations of suppliers, oversupply of these vaccines in the United States has become a growing problem during the past influenza seasons (Fig. 2).

Figure 2: US influenza vaccine supply versus demand for the influenza seasons 2003/2004–2008/2009.

This has triggered a growing commoditization of influenza vaccines. Prices, which increased from below $2 per dose in the late 1990s to $12 per dose at the peak of the business in 2007, have fallen over the past 2 years to reach a new low of $8.60 on average in 2009 (Ref. 3). To reverse this price decline, reduce the commodity nature of influenza immunizations and improve their market shares, vaccine developers are turning to new technologies that could offer product differentiation.

Developments in adjuvant technology

One key area of interest is an enhancement of vaccine immunogenicity through adjuvants. The key advantage in the influenza sector is a reduction in the amount of antigen required for protective immunization. This so-called dose-sparing effect helps to increase the number of available vaccine doses. This is particularly important in a pandemic, when the supply, limited by manufacturing capacity, cannot meet the demand. Another advantage of adjuvanted vaccines is their potential for improved immunogenicity in the elderly, which is a key unmet need. Novartis and GSK are currently furthest advanced in developing these technologies for influenza. Both companies have already received European approval to make products using their oil-in-water-based emulsions MF59 and AS03, respectively. By contrast, gaining US approval for adjuvanted vaccines has proven difficult, with the FDA adopting a conservative position, presumably owing to a lack of data on the long-term safety profile of novel adjuvants. The current influenza A (H1N1) pandemic has rejuvenated interest in adjuvanted influenza vaccines, with several governments investing into large adjuvant stockpiles. Clinical studies investigating potential benefits of various adjuvanted pandemic influenza A (H1N1) vaccines were initiated. However, clinical trials of non-adjuvanted H1N1 vaccines have now demonstrated sufficient immune responses, indicating that at least in the early stages of vaccination against H1N1, adjuvants will not play a part in the US.

Improving manufacturing techniques

A further opportunity for product differentiation is the influenza vaccine manufacturing process. With the exception of Novartis's Madin–Darby canine kidney (MDCK) cell-based vaccine Optaflu, which gained European Union approval in 2007, all marketed seasonal influenza vaccines are still manufactured in chicken eggs. This process is not only lengthy and inflexible, but would also be unsuitable in the event of an avian influenza pandemic. To provide faster and more flexible alternatives, numerous companies are developing alternative production systems. Besides Novartis, Baxter is the only other player to have gained European approval for a cell-based influenza vaccine — its mock-up pandemic vaccine Celvapan, which is manufactured in Vero cells (a kidney epithelial cell line derived from African green monkeys). During the current pandemic, both companies are set to gain substantial commercial windfalls from using this faster production technology for H1N1 vaccine production. Smaller players, including Protein Sciences and Novavax, are developing production systems in insect cells based on the baculovirus system. Other strategies in earlier stages of development include the use of bacterial and plant expression systems.

The current influenza A (H1N1) pandemic has boosted vaccine stockpiling contracts. Established manufacturers, particularly Novartis and GSK, are likely to draw the largest commercial benefit. Besides its direct impact on pandemic vaccine sales, H1N1 will also influence the future development of the seasonal influenza vaccines market. We think that the most likely outcome for future sales development will be a transient boost triggered by the current pandemic. Seasonal influenza vaccine uptake will increase considerably over the next two influenza seasons, with sales figures rising to $4 billion by 2010–2011 across the seven major markets. Once the pandemic has passed, however, we expect a period of stagnation caused by declining seasonal vaccination coverage in most population groups (Fig. 3). By 2018–2019, the seasonal influenza vaccine market size could reach $5 billion across the seven major markets, driven by further extensions of vaccination recommendations1. Sanofi Pasteur, which was market leader in 2008 with global influenza vaccine sales exceeding $1 billion5, will maintain its top position; however, we think that GSK and Novartis will increase their share owing to their competitiveness in new technologies such as adjuvants and cell-based manufacturing.

Figure 3: Seasonal influenza vaccine market size and forecast.

Data for the seven major markets for the influenza seasons 2005/2006–2018/2019. Data from Ref. 1.

Moderna Announces Positive Phase III Data For Covid-19/Influenza MRNA Vaccine

Moderna has announced positive Phase III data for its Covid-19/influenza combination vaccine, mRNA-1083. The investigational combination messenger RNA (mRNA) vaccine generated statistically significant higher immune responses in relation to the licensed comparator vaccines used in the randomised, observer-blind, active control study among 8,000 adults ages 50 years and older. This development comes less than two weeks after Moderna received FDA approval for the first mRNA respiratory syncytial virus (RSV) vaccine, mRESVIA, further demonstrating the potential of mRNA technology in combatting infectious diseases.

mRNA-1083 combines the mRNA-1010 seasonal influenza vaccine candidate with the mRNA-1283 next-generation Covid-19 vaccine candidate. At this time, mRNA-1083 is poised to be the first Covid-19/influenza combination vaccine and the first mRNA influenza vaccine on the market.

Moderna reported that a single dose of mRNA-1083 met immunogenicity non-inferiority criteria versus the licensed comparator vaccines: Sanofi's Fluzone High-Dose and GSK's Fluarix for influenza, and Moderna's Spikevax for Covid-19. Furthermore, mRNA-1083 generated statistically significant higher immune responses against the influenza strains H1N1, H3N2, and B/Victoria, as well as SARS-CoV-2. In the study group of adults ages 50–64 years, the geometric mean ratios (GMRs) of mRNA-1083 compared to Fluarix were 1.414 (A/H1N1), 1.380 (A/H3N2), and 1.216 (B/Victoria). The GMR of mRNA-1083 compared to Spikevax was 1.308. In the study group of adults ages 65 years and older, the GMRs of mRNA-1083 compared to Fluzone High-Dose were 1.155 (A/H1N1), 1.063 (A/H3N2), and 1.118 (B/Victoria). The GMR of mRNA-1083 compared to Spikevax was 1.641. MRNA-1083 also met non-inferiority criteria against the B/Yamagata strain of influenza, but this strain is no longer recommended for the composition of seasonal influenza vaccines. The investigational combination vaccine displayed an acceptable safety and tolerability profile, with the most commonly reported adverse reactions being injection site pain, fatigue, myalgia, and headache.

The development of a Covid-19/influenza combination vaccine could be advantageous to patients, as it would decrease the number of injections needed to provide sufficient protection against multiple respiratory illnesses. Likewise, the development of a combination vaccine is strategic for pharmaceutical companies, as successful uptake of the vaccine can translate to significant market shares under multiple indications.

Key opinion leaders (KOLs) interviewed by GlobalData have expressed positive opinions on both the development of a Covid-19/influenza combination vaccine and the advancement of vaccines for infectious diseases due to mRNA technology. MRNA vaccines require a shorter production time and have the potential to incorporate large numbers of antigens. Therefore, they may be more efficacious than traditional vaccines.

Story continues

According to GlobalData, there are over 90 mRNA vaccines for infectious diseases in late-stage development (Phases II–III) globally. These include vaccines for Covid-19, RSV, influenza, cytomegalovirus, tuberculosis, malaria, mpox, meningitis, norovirus, shingles, and Lyme disease. Among these are combination vaccines for Covid-19/influenza and COVID-19/RSV.

If approved, Moderna's Covid-19/influenza combination vaccine will be an important addition to the vaccine market. The positive Phase III data on the combination provides further validation of how mRNA technology is advancing the infectious diseases pipeline.

"Moderna announces positive Phase III data for Covid-19/Influenza mRNA vaccine" was originally created and published by Clinical Trials Arena, a GlobalData owned brand.

The information on this site has been included in good faith for general informational purposes only. It is not intended to amount to advice on which you should rely, and we give no representation, warranty or guarantee, whether express or implied as to its accuracy or completeness. You must obtain professional or specialist advice before taking, or refraining from, any action on the basis of the content on our site.

View comments

---