I cannot stress enough on the importance of looking at the raw scientific data as oppose to articles published by news outlets when to comes to COVID19 vaccines/ drugs-related information. These articles are often bias and inaccurate. However, I can totally understand that these data can be way too convoluted to be understood by the public. Therefore, I thought that it will be a good idea to take a closer look at the preliminary report on Moderna’s mRNA-1273, published just last week in the New England Journal of Medicine and attempt to explain the Science objectively and to give my two-cents worth.
A quick background about the mRNA-1273 vaccine
mRNA-1273 is manufactured by Moderna U.S.A. and it composed of a full-length mRNA encoding for a stabilized form of the viral spike glycoprotein (s protein) encapsulated in a lipid nanoparticle (Figure a).
Right off the back, how can be tell when a vaccine works? Simply put, if a person who receives a vaccine produces an antibody response against it, it is a good indicator of a vaccine that works (Figure b). In the clinical paper, they have three main parameters to measure efficacy of the vaccine:
1. Binding antibody responses (The body is able to produce antibodies that targets and binds on to the viral s protein)
2. Virus neutralization responses (The antibodies that bind are able to elicit the destruction of the virus particles they are bound to)
3. T cell responses (The body was able to also T cells, another group of important immune cells)
What other important details do we need to take note of?
1. The trial design and profile of the participants
2. The titer/ the dose of the vaccine
3. Adverse side-effects from the vaccine
Trial design
45 healthy participants aged 18-55 years were given two injections of mRNA-1273 28 days apart at a dose of 25ug (low), 100ug (medium) or 250ug (high). The average age across the different groups was ~ 30 years. Injections were delivered to the deltoid muscle. Follow-up visits were scheduled for 7 and 14 days after each vaccination and on days 57, 119, 209, and 394.
Results
1. None of the participants had fever after the first dose. About half the participants in the medium and high dose groups reported fever after the second dose. Local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site but were classified as mild/ moderate.
2. The vaccination was able to stimulate the production of s protein binding-antibodies in participants. The higher the dose of the vaccine, the more antibodies were produced by participants. This is a good indicator that the vaccine works but the difference between the medium and high dose groups were considerably mellow.
3. After the second vaccination, all the participants were able to produce virus-neutralization response but the magnitude of response were similar between medium and high dose groups.
4. Medium and high doses of vaccine were able to stimulate CD4 T cell responses, with strong biases towards Th1 cytokines.
Confounding variables you need to know
This study is not perfect and it is as important to understand the caveats as it is the results.
1. Participants were not screened for SARS-CoV-2 infection before enrollment.
- This means that we cannot rule out the possibility that some of the outcomes observed were results of prior infection i.e. if a participant had been infected and was asymptomatic, their immune system would’ve already have the ability to effectively produce antibodies against s protein regardless of vaccination.
- The paper did mention that none of the participants were able to produce antibody neutralizing responses before vaccination which could indicate that none of the participants have been infected prior to the trial but is not definitive.
2. 89% of participants are white
- The lack of participants of other race and ethnic groups means that we are unsure if the outcomes observed are representative.
3. Participants are all adults
- Will the vaccine elicit a similar outcome in babies and children? Will it be safe for them?
4. This is not a human challenge trial
- I have briefly introduced and explain about HCT in my infographic ‘What is taking so long?’. Ultimately, testing blood samples participants in the lab is still different from how the body will response when infected by the actual virus and also how will the responses change with different severity of infection?
My thoughts
The vaccine scored well in all the three parameters, with the medium dose group performing the best. Using a high dose of the vaccine did no more good than harm. I would say that based on the raw data, the vaccine has passed with flying colours. However, my overall position is still one that is skeptical because of those confounding variables I have raised. They will need to address those concerns in their upcoming study.
As what Heaton, 2020 mentioned in her editorial article, we are witnessing ‘the compression of 6 years of work into 6 months.’, I think it is better to err on the cautious side especially when it comes to a vaccine that will be used to immunize the entire world.
What’s next?
Amidst the intense race and global competition of COVID19 vaccine development, mRNA-1273 has entered Phase 3 clinical trials in the U.S. with a target enrollment of 30,000 participants.
Figure legend
a. Left: Structure of the SARS-CoV-2 virus; spike glycoproteins are found on the viral envelope. Right: The mRNA-1273 vaccine is a nucleic acid vaccine composed of viral mRNA that codes for the viral S protein.
b. Efficacy of mRNA-1273 is determined by the presence of a body’s antibody responses towards the viral S protein.
Resources
Biorender (online platform for scientific figure making)
NIH Clinical trial identifier - NCT04283461
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