A big week for mRNA COVID-19 vaccines: Five key developments
Pfizer and Moderna’s mRNA vaccines have both reported around 95% efficacy this week: Moderna through its interim analysis and Pfizer with the conclusion of its Phase 3 study which met all primary efficacy endpoints.
The two developers are the first to release Phase 3 results for COVID-19 vaccine candidates. Here's five key takaways from their reports.
1) Efficacy: 'This is a very impressive result'
The main headlines this week have been around efficacy. Pfizer now reports 95% efficacy; Moderna 94.5%.
Although these are still early indications of efficacy, they are far above efficacy rates for influenza: with the US Center for Disease Control and Prevention (CDC) estimating flu vaccines reduce the risk of sickness by 40-60%.
The FDA wants to see 50% efficacy in COVID-19 vaccines. A study published in the American Journal of Preventive Medicine last month suggested a vaccine should have an efficacy of at least 70% to prevent an epidemic and of at least 80% to largely extinguish an epidemic without any other measures such as social distancing.
Pfizer’s protocol wanted to see 62.7% efficacy for the first 92 cases. “We dramatically exceeded that threshold by reporting more than 90% vaccine efficacy,” reported the company. Moderna’s study protocol, meanwhile, simply wanted to see the interim analysis give ‘early detection of reliable evidence that VE [vaccine efficacy] is above 30%’. It got 94.5%.
Yesterday Pfizer used its Phase 3 primary analysis to pinpoint its efficacy figure as 95%. The trial of more than 43,000 people identified 170 confirmed cases of COVID-19, with 162 cases in the placebo group and 8 in the vaccine group.
“An efficacy of 50% (with a lower bound of 30%) was the benchmark for approval and most commentators would have predicted 60-70% at best beforehand," comments Dr Adam Barker, healthcare analyst at Shore Capital, responding to the primary analysis.
"Of course, this efficacy could change over time as more data is collected on the vaccine as it is rolled out and we still don’t know the duration of the immunity it confers. And we still don’t know whether the vaccine can prevent infection/onward transmission or just reduce symptoms. This question will be answered using antibody data in the weeks and months to come.
"Regardless, this is a very impressive result.”
Pfizer also highlights the efficacy of the vaccine in older people: citing almost equivalent efficacy (94%) in people over 65 years old.
Another key development is that both Pfizer and Moderna have now released figures for severe COVID-19 encountered in the study: albeit from a small sample size.
Pfizer’s primary analysis included 10 severe COVID-19 cases; with nine in the placebo group. Moderna’s interim analysis saw 11 severe cases, all in the placebo group. If the vaccines are able to reduce severe COVID-19, that will be what reduces the pressure on hospitals and healthcare systems.
Both Pfizer and Moderna champion the diversity of their study cohorts: hoping to show the vaccine is effective across various groups. Pfizer states that efficacy is 'consistent across age, gender, race and ethnicity demographics'.
For Pfizer, the efficacy data is a great milestone. “This is a tremendous moment for us because it gives us greater confidence in our vaccine candidate and brings us a significant step closer to delivering a vaccine to help prevent further spread of SARS-CoV-2,” the company told us. “It also comes at a time when the world needs it most with infection rates setting new records.”
BioNTech CEO Ugur Sahin, M.D. adds: “Our objective from the very beginning was to design and develop a vaccine that would generate rapid and potent protection against COVID-19 with a benign tolerability profile across all ages. We believe we have achieved this with our vaccine candidate BNT162b2 in all age groups studied so far."
2) Regulatory approval timelines come into focus
However, efficacy is just one of three key areas vaccine developers need to set out to the FDA in an Emergency Use Authorization (EUA) request. They will also need to prove the vaccine is safe (the FDA wants two months of safety data, which Pfizer has now reached this week and Moderna looks set to obtain in the coming weeks) and prove that it can manufacture the vaccine consistently to high standards.
Pfizer expects to submit its request for EUA ‘in the coming days’; Moderna in ‘the coming weeks’.
Both, meanwhile, have started rolling reviews with other regulatory agencies such as Europe’s EMA (The EMA started a rolling review for Pfizer last month October and for Moderna this week)
At a glance: Pfizer and Moderna's vaccine candidates
Pfizer/BioNTech: BNT162b2 | Moderna: mRNA-1273 | |
Efficacy according to Phase 3 study | 95% (primary efficacy analysis with 170 COVID-19 cases) | 94.5% (interim analysis with 95 COVID-19 cases) |
Safety according to Phase 3 interim analysis | 'The DMC has not reported any serious safety concerns' | 'A review of solicited adverse events indicated that the vaccine was generally safe and well tolerated' |
Phase 3 trial details | More than 43,000 participants aged 12+ with Phase 3 trials in the US, Brazil, South Africa and Argentina (vaccine and placebo) | 30,000 participants aged 18+ in the US (vaccine and placebo) |
The tech in brief | 3 LNP-mRNAs | LNP-encapsulated mRNA |
EUA request submission date | 'within days' | 'in the coming weeks' |
Other regulatory reviews in place | EMA rolling review in progress | EMA, Health Canada, MHRA and Swissmedic rolling reviews in progress |
Notable supply agreements in place | US, EU, UK, Australia, Canada, Japan | US, UK, Canada, Qatar |
Long term storage requirements | Ultralow temperature freezers for up to 6 months. Transportation at -70°C (-94 F) for up to 10 days | Standard freezer temperatures of -20°C (-4°F) for up to 6 months |
Short term storage | Standard refrigerator temperatures of 2° to 8°C (36° to 46°F) for 5 days | Standard refrigerator temperatures of 2° to 8°C (36° to 46°F) for 30 days |
2020 production capacity | 50 million | 20 million doses |
2021 production capacity | 1.3 billion | up to 1 billion doses |
NB: The above information is based on press announcements from Pfizer and Moderna and is not intended to be an exhuastive list of agreements or details.
3) Temperature: Pfizer reveals how it will deal with ultra-cold requirements
One key advantage of Moderna’s vaccine is its temperature requirements. Storage and transporation requirements, updated by Moderna this week, show the vaccine can be stored at standard freezer temperatures for up to 6 months, compared to the ultra-low temperature freezers Pfizer requires.
Pfizer, however, is well aware of the challenges the vaccine’s storage requirements present and thus has incorporated them into its COVID-19 vaccine planning.
“We have specially designed, temperature-controlled thermal shippers utilizing dry ice to maintain recommended storage conditions up to 10 days,” the company told BioPharma-Reporter. “The intent is to utilize Pfizer-strategic transportation partners to ship by air to major hubs within a country/region and by ground transport to dosing locations.
“We will utilize GPS-enabled thermal sensors in every thermal shipper with a control tower that will track the location and temperature of each vaccine shipment across their pre-set routes. These GPS-enabled devices will allow Pfizer to proactively prevent unwanted deviations and act before they happen.
“Once a POU receives a thermal shipper with our vaccine, they have three options for storage. Ultralow temperature freezers are commercially available now and can extend shelf life for up to 6 months. The vaccine can be stored for five days at refrigerated 2-8°C conditions. Or they can utilize the Pfizer thermal shippers (that doses will arrive in) which can be used as temporary storage units by refilling with dry ice for up to 15 days of storage.”
4) Multiple mRNA candidates edge forward
As well as being the first COVID-19 vaccine developers to report Phase 3 results, both Pfizer and Moderna are exploring new technology in their mRNA candidates.
Unlike conventional vaccines, which take time to produce by growing weakened or inactivated forms of the virus, RNA vaccines can be constructed quickly using only the pathogen's genetic code. By introducing a mRNA sequence with genetic instructions into the body, a patient can produce their own vaccine antigens and generate an immune response.
As BioNTech’s CEO puts it, the efficacy reported this week ‘highlights the potential of mRNA as a new drug class’.
For Pfizer and Moderna, FDA and other global regulatory approvals are in sight. This could mean distribution starts by the end of the year, although only in limited quantities. Next year Pfizer wants to product 1.3 billion doses and Moderna 1 billion doses.
Eyes will now turn to other mRNA vaccines against COVID-19. The next COVID-19 mRNA candidate in line is CureVac’s CVnCoV, which is currently in Phase 2 trials and expects to enter a Phase 2b/3 clinical study before the year is out.
The German company’s candidate is currently in a Phase 2a clinical trial in Peru and Panama. Phase 1 interim data reported this month showed that CVnCoV was generally well tolerated across all tested doses and induced strong antibody responses in addition to first indication of T cell activation.
The US’ Arcturus Therapeutics also has a mRNA COVID-19 vaccine candidate: which is currently in a Phase 1/2 clinical trial in Singapore. And while Sanofi's lead candidate is its recombinant vaccine with GSK, it also has a mRNA candidate in pre-clinical trials with Translate Bio.
5) Speed of Phase 3 trials - and vaccine development as a whole
It’s been said many times: the speed of vaccine development in the fight against COVID-19 has been remarkable.
The last week has shown the pace of clinical trials has also accelerated: the growing number of cases of COVID-19 over the last couple of months has meant Pfizer and Moderna accrued cases in their Phase 3 studies quicker than expected.
Pfizer had expected to reach its 164 cases – the point for its final primary and secondary endpoint efficacy analysis – next month. Instead, it was in a position to release this data yesterday. Moderna, meanwhile, reached 95 cases instead of 53 for its interim analysis and is now working towards 151 cases for its primary analysis.
With Pfizer becoming the first COVID-19 vaccine to reach the final efficacy analysis mark, taking a step back shows how far vaccines have come since the SARS-CoV-2 genome sequence was published in January.
“Pfizer’s successful Phase 3 trial of a COVID-19 vaccine marks the final step (before regulatory submission) of a quite remarkable journey," says Dr Adam Barker of Shore Capital.
"Vaccines usually take 5-15 years to develop and are extremely complex products, which means the global scientific community and pharmaceutical industry has pulled off a incredible feat in getting a candidate to this stage in only one year. Today is another day to marvel at the global collaboration of the scientific community and to be thankful for all of those volunteers who put their hand up to take part in vaccine trials
“Collectively, the vaccine announcements in the past two weeks have been a huge result for humanity. No doubt there will be difficulties along the way and questions still remain (e.g. how long will vaccine-mediated immunity last?) However, having concerns about how to roll out a vaccine with 95% efficacy is a position few people (the author included) thought we’d be in at this stage. This is a very welcome problem indeed, and another major step in bringing the COVID-19 pandemic to an end.”
