by Reynald Castaneda in London.
Moderna Phase I mRNA-1273 vaccine drew cautious reviews on its potential to trigger immunogenicity for protection against Covid-19. From using mRNA as a vaccine strategy, to the antigen choice of the virus’ spike protein, interviewed experts noted several advantages but in the same breath voiced many concerns.
As of April 8, there were 115 vaccine candidates in varying stages of preclinical testing, with 78 confirmed as active programs, as per the Coalition for Epidemic Preparedness Innovations. Vaccine development has grabbed public attention as it could be a critical element in easing pandemic-related restrictions, but experts noted a vaccine in 12-to-18 months is only possible in a best-case scenario. Moderna CEO Stéphane Bancel told Goldman Sachs that under emergency use, a vaccine could be available to some people like healthcare professionals in the fall of 2020, as per news reports on 25 March.
However, that while mRNA vaccine manufacturing is relatively straightforward and is an important consideration for a pandemic of this scale, the caveat is that the mRNA may code for enough irrelevant proteins that would negatively impact immunogenicity. It is also still challenging to identify how much neutralising antibodies are needed for protection. There can be variation between assays, making it challenging to have a uniform antibody titre target. Furthermore, the quality of antibodies generated may be variable, and in vitro confirmation of antigen efficacy may not be replicated in humans.
The choice of SARS-CoV-2’s spike protein as the vaccine’s antigen is logical, as it is shown to be immunogenic based on experience with comparable coronaviruses, and the spike is an important feature of the virus’ life cycle. However, experience in other coronaviruses may not apply as antibodies are highly specific, and vaccines that offer long-term protection are those that feature more than one element of the pathogen.
The mRNA-1273 Phase I trial (NCT04283461), funded by the National Institute of Allergy and Infectious Diseases (NIAID), recruited its first patient on 16 March and has a six-week recruitment period, and efficacy endpoints measured at day 57. Moderna’s chairman, Noubar Afeyan, told PMLive on 3 April that its vaccine could begin Phase II trials in spring or early summer. The company, which has a $15.4bn market cap, did not respond to a request for comment. NIAID declined an interview request but forwarded previously published media releases.
Manufacturing speed an advantage but immunogenicity strength could be at risk
Relative speed of production of mRNA vaccines compared with other vaccine types is a clear advantage, said Chantal Pichon, PhD, professor, molecular and cell biology, University of Orléans, France. Besides being able to manufacture sufficient quantities for clinical trials, scaling up is a primary concern for addressing a pandemic, noted Mark Kane, independent immunisation policy consultant in Seattle, Washington.
mRNA vaccines are fully synthetic, so once a target antigen’s sequence is known, a vaccine can be produced quickly, and the same infrastructure can be used to produce other mRNA vaccines that contain a different sequence, explained Norbert Pardi, PhD, research assistant professor, Department of Medicine, University of Pennsylvania. In contrast, vaccines that carry proteins to stimulate the immune system have additional steps that include cell line and purification procedures, which can make manufacturing more of a challenge, Pardi said.
However, the lack of a purification step could be an efficacy drawback, noted Andrew Ward, PhD, professor, Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, California. Since the proteins mRNA vaccines generate are not purified, a notable percent may not be the type of protein that triggers an immune response, Ward explained.
It is also challenging to pinpoint an immunogenicity benchmark for mRNA-1273, as testing protective efficacy is not straightforward, Pardi said. An FDA guideline proposed 1:320 as the optimum neutralizing antibody titre. But in reality it is hard to identify the appropriate neutralising antibody titre, Pichon noted. For starters, there are many different neutralising antibody assays and readouts could be different, Pardi said. Comparing vaccines in terms of antibody titres is only possible if there is an optimised, universal assay, he added.
Furthermore, even if the titre is high enough, the jury is still out on whether the aforementioned relevant protein antigens trigger the right antibodies, Pichon said. In addition, the antibody titre needed to protect against mild symptoms may be different from what’s needed to protect against severe symptoms, Ward added. In convalescent plasma investigations, identifying whether a patient’s plasma has the necessary antibody titre level is based on those who were severely ill, who are more likely to have the highest level of therapeutic antibodies, said Dr John Roback, Medical Director, Blood Bank, Emory University Hospital, Atlanta, Georgia. Severe patients have more ideal antibodies, as the patient’s immune system has refined them over time, he added.
There are reports of recovered Covid-19 patients either being re-infected or having a reactivation of the virus, said Alan Parker, PhD, reader in virology, School of Medicine, Cardiff University. However, it is nebulous how many were false positives and in those that were real, what their antibody titres were, he explained.
Additionally, the fact is that overall there is limited information on SARS-CoV-2, Ward added. Experience with SARS-CoV-1 and MERS-CoV may not be applicable, because they caused relatively small outbreaks, which limited investigations, he said.
Any Phase I data that shows mRNA-1273 can induce an antibody response would be a good start, Pardi added. But the next step is looking at the quality of these antibodies, which can be tested via in vitro neutralising assays, Pardi said. And even then, experience in vitro may not reflect what could happen in humans, considering there are multiple factors that contribute to vaccine protection, Pardi added.
A 45-patient Phase I trial is standard in vaccine studies primarily investigating safety, Parker added. The Phase I trial has primary endpoints covering adverse events, while efficacy is measured through secondary endpoints looking at increase of mean antibody titre and immunoglobulin G (IgG) as well as percent of seroconverted patients at day 57.
The trial is investigating 25mcg, 100mcg and 250mcg of mRNA-1273 administered via injection in the deltoid muscle on days 1 and 29. In general, the higher dose may induce better protection, Pardi said. Yet, there are still enough knowledge gaps on the mechanism such that even a lower dose may induce a sufficient immune response, he noted. Dose potency also depends on the route of administration and structure of the mRNA, Pichon added.
Spike protein a critical virus element but may need immunogenicity boost
There is also the risk that mRNA-1273’s spike protein of SARS-CoV-2 may not be the most immunogenic choice for a vaccine target, Pichon said. It is possible for mRNA vaccines to code for more than one antigen, Pardi added. mRNA-1273 has the encoding for SARS-CoV-2’s full-length, prefusion stabilized spike protein only. But there is still the chance that SARS-CoV-2’s viral envelope may be more immunodominant, Parker noted.
Still, Pardi and Ward agreed SARS-CoV-2’s spike protein has the potential to offer enough immunogenicity, based on experience with SARS-CoV-1 and MERS-CoV. Although there are no licensed vaccines for these coronaviruses, there is a bounty of preclinical investigation that helps in figuring out ways to engineer an mRNA vaccine, Pardi said. SARS-CoV-1, MERS-CoV and SARS-CoV-2 are comparable enough that if vaccines were developed during the SARS and MERS outbreaks, those vaccines could have been used in the ongoing pandemic and could have delivered some degree of protection versus SARS-CoV-2, he added.
An advantage of the mRNA vaccine’s synthetic manufacturing is that the spike antigen could be modified to make it even more immunogenic, Pardi added. Additionally, the spike protein is an important part of SARS-CoV-2’s life cycle, as it recognises host cells to be infected, Ward noted. The spike protein is also presented outside of an infected host cell, which helps the immune system zero in on what cells to attack, he added. While SARS-CoV-2’s mutation rate is currently unknown, mutations were not observed with SARS-CoV-1 and MERS-CoV and so is an unlikely issue, Pardi said.
However, while there may be similarities between SARS-CoV-1, SARS-CoV-2 and MERS-CoV, there is still the risk that there are subtle amino acid differences between their spike proteins, Ward said, adding a key feature of antibodies is their specificity.
Also, there are still knowledge gaps regarding whether an mRNA vaccine containing the spike protein code would be enough to offer long-term protection, Ward said. Vaccines that are able to offer durable protection are live-attenuated or inactivated vaccines, which feature multiple components of the virus, he noted.
With regards to safety, based on all available data, mRNA vaccines are considered generally safe, Ward added. Perhaps local site and some systemic reactions will need monitoring, Kane noted.
However, one notable side effect that needs investigation is if mRNA-1273 could trigger the production of non-neutralising antibodies, which can lead to antibody-dependent enhancement (ADE), Ward said. ADE was experienced in SARS-CoV-1 patients who either had high antibody responses against SARS-CoV-1’s spike protein or received plasma transfer, Parker noted.
Yet, Parker added, ADE is a potential issue for any vaccine approach. In fact, some degree of non-neutralising antibodies may be needed as it could help boost cell-mediated immune response to produce cytotoxic lymphocytes to kill infected cells, Pichon explained.
Reynald Castaneda is Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.