Moderna’s recent announcement of interim results from the ongoing clinical trial on its vaccine candidate, mRNA-1273, reveals data promising enough for the phase 1 study to move forward to the next phase. The study was designed to determine the safety of the vaccine while examining the immunogenicity at various doses. Despite the small number of participants, the study is seen as promising because an immunogenic response was observed with all three doses of the vaccine. The results demonstrated a positive dose-response curve, which is very reassuring. We assume that the 25-microgram dose met the World Health Organization (WHO) threshold for immunogenicity, and the 100-microgram exceeded that threshold. However, the full significance of the response won’t be known until phase 3 pivotal studies can demonstrate efficacy (protection from disease). The scope and design of this study phase limits insight we can draw from the preliminary results, but there are more than a few reasons for cautious optimism.
The Safety Profile
The data from all the patients enrolled and immunized revealed that the vaccine was well tolerated overall at all dosages; some adverse events (AEs) were noted that are common to most vaccines at various doses of the vaccine. A participant receiving the 100-microgram dose experienced localized redness at the injection site, which is a common observation with many vaccines. Fever and myalgia are grade-three AEs that were observed at the 250-microgram level. Again, these kinds of events are not unusual for vaccines under development. Reassuringly, the events were transient and self-resolving without the need for medical intervention. Furthermore, serious grade-four AEs were not observed.
Binding and neutralizing antibody titers from 8 of the 45 individuals in the 18-to-55 age group were announced. The binding antibody titers were stated to be more than fourfold for seroconversion, and the neutralizing antibody titers were more than that seen in convalescent sera. In the absence of actual data and the absence of data supporting a protective neutralizing antibody substantive. This needs to be replicated in the over-55 age group, followed by in-depth data analysis and a determination of geometric mean titers from all study subjects using validated ELISA binding and PPRN neutralizing antibody assays. At such an early stage in the trial (day 43), we can only draw limited insight on the durability of the immune responses from the data. As the study proceeds, the max titers, AEs, and durability of immunity can be examined at three, six, and twelve months.
Vaccine Durability
An important question is whether the durability of the Moderna vaccine varies with age, dose, or other factors; the interim results announced do not address this question. If the immune titers begin to drop, you can record how much of a drop you observe at each interval. Durability limited to three months is problematic, but it’s unlikely that the neutralizing antibody titers will simply return to zero. On the other hand, the titers could plateau and last for at least a year, producing the desired outcome.
Delving Deeper: Stability and Potency
Another factor to consider when looking at vaccines is their stability – in other words, determining if the potency persists well beyond six to twelve months. The answer for the current candidates is unknown, as we haven’t made and stored these vaccines long enough. Besides, it goes beyond just proper storage. Do the lipid nanoparticles start dissociating? If they do, then the messenger RNA (mRNA) becomes vulnerable to disruption, producing intermediate metabolites as it degrades. These metabolites can, in turn, interfere with the immunogenicity.
Commercial manufacturing, which has not been performed by any manufacturer of mRNA vaccine candidates for any pathogen to date, brings its own set of unique challenges. A vaccine produced at such a large scale should be tested immediately and appropriately stored until used. Manufacturers use a slightly higher dose than necessary because of potential stability issues that may arise from prolonged storage. Influenza vaccines, for example, may contain a bit more hemagglutinin and neuraminidase than what you see on the label because some of those vaccines are manufactured, then stored in vials for over a year before they’re used. Both the Food and Drug Administration (FDA) and manufacturers want to ensure the vaccines still elicit good immune responses long past their manufacture date. Usually, it takes years to iron out these practical manufacturing and vaccination issues, and in this case, we’re taking only months. Moderna has partnered with Lonza with a view to producing a robust and controlled manufacturing process that transcends some of the challenges of commercial manufacturing, yet Lonza has not produced mRNA vaccines at commercial scale previously.
Long-Term Impact
There will likely be a significant number of people who receive this vaccine before 12-month data becomes available. A minimum ask would be at least 50% efficacy, but hopefully closer to 75% efficacy, like we saw with some of the Ebola vaccine candidates. I expect the FDA to contrast the risks with the likely benefits, and if a 50% efficacy is seen at the six-month mark and the vaccine is well tolerated, it may move forward.
What Else Is Out There?
There’s a high amount of anticipation when it comes to the SARS-CoV-2 vaccines, and the Moderna trial gives hope that other vaccine candidates will provide positive results as well. The bottom line is that none of these studies have gone past phase 1 but still hold considerable promise based on initial results. CureVac and Moderna are RNA technology companies that are betting the house on one vaccine candidate, with their proprietary liposome nanoparticle technology.
Other companies, such as Pfizer with BioNTech, are more conservative, looking at four different candidates in their phase 1 study. Those will be whittled down to just one candidate and one dose, hopefully before phase 3 studies. Pfizer has been pursuing mRNA technology for several years with BioNTech to develop a universal influenza vaccine. They simply transferred that capability into COVID-19 vaccine development. They’re using a self-amplifying mRNA technology (SAM) that allows the making of more copies of mRNA within the cell that the mRNA gets into. This approach may produce higher immunogenicity. Pfizer may not have a candidate chosen before Moderna does, but it may actually have a vaccine candidate that works better.
Sanofi, which has two different vaccine approaches – recombinant protein + adjuvant and mRNA – is taking a different mRNA approach with a technology that Translational Bio offers. The liposome nanoparticle technology targets the nanoparticles directly to the antigen-presenting cells, delivering a payload of the vaccine immediately for presentation to the rest of the immune system. This could be a significant advantage, as the immunogenicity from this strategy may be greater than that seen with the other mRNA vaccine candidates that are not so targeted. The disadvantage is that Sanofi, like other mRNA vaccine developers, has not been pursuing mRNA vaccine technology for long, but it does have experience in running large-scale clinical programs and should not be discounted. It may not be out of the gate first, but it may certainly be a winner at the end.
Other Vaccine Platforms
Oxford University developed an adenovirus vector-based vaccine. The results from nonhuman primate studies do not tell us satisfactorily that its approach is going to work in humans. Animal models for SARS-CoV-2 are not fully representative of the human disease, and the durability of the immune response in humans is not guaranteed.
Novavax, with its recombinant protein + adjuvant vaccine approach, should be able to produce a highly immunogenic and durable vaccine in large amounts buoyed by manufacturing partnerships and external funding.
This article is adapted from the May 20, 2020, GLG teleconference “Moderna’s SARS-CoV-2 Vaccine.” If you would like access to this teleconference or would like to speak with Dr. Robinson or any of our more than 700,000 experts, contact us.
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