Leading COVID-19 vaccine candidates rely on new genetic technologies that have fast-tracked development and testing. This video explains the principles underlying the leading DNA, messenger RNA (mRNA), and viral vector vaccine candidates, and how they might induce immunity to SARS-CoV-2 infection.
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Researchers are racing towards the goal of delivering a safe and effective vaccine that could curb the COVID-19 pandemic. And production scale-up for some of the vaccine candidates has already started. Consider the US government's Operation Warp Speed:
[Robert Redfield, MD:] You know I spent time in the military, so I like that concept of focusing on a mission. And the mission is to have a vaccine available to the American public by January 2021. We're on an accelerated course here that I've not witnessed before.
One of the reasons why this vaccine search is breaking records is because most of the frontrunners--and nearly all the vaccines in the Warp Speed portfolio--are based on next-generation technologies that can be developed and scaled up more quickly than conventional vaccines. These new technologies are genetic vaccines and viral vector vaccines.
These technologies--also called platforms--have been in development for decades. A lot of the investment in them has specifically focused on their potential to combat emerging infectious diseases. And COVID-19 is putting that potential to the test. Let's take a look at how they work, and how they're different from conventional vaccines.
In these pictures from 1953, the scientists are developing an influenza vaccine. They're injecting viruses into fertilized eggs, which are then incubated to allow the virus to replicate within the eggs. Growing the virus is necessary for developing live attenuated virus and whole inactivated virus vaccines--these are the two classic approaches where the virus is either weakened or killed. These approaches are still in use today, although different cell cultures are most often used instead of eggs.
But since those photos were taken, huge advancements in the field of vaccinology have introduced multiple other approaches to developing vaccines. Here are the major types of vaccines being deployed against COVID-19. Unlike the two classic vaccines, these four types, which include the next-generation platforms as well as more conventional approaches, don't require researchers to handle any of the actual virus.
[Anthony S. Fauci, MD:] The Chinese, when they made the diagnosis and showed it was a coronavirus, they put the sequence up on a public database. So today you don't need the virus in hand. All you need is a sequence.
This is that published sequence for SARS-CoV-2. Because of previous research into SARS-1 and MERS, researchers knew that they could focus initial attention on the S protein, also known as the spike.
The spike is the protein that studs the surface of the SARS-CoV-2 virus. It's also necessary for viral entry into human cells. So a vaccine that exposes the immune system to just the spike should induce a protective immune response. And that's the strategy behind the majority of COVID-19 vaccine candidates, which use both next-generation and more conventional approaches. The scientific way to put this is that the spike is the target antigen in these vaccines.
Where the next-generation vaccine platforms differ from those more conventional vaccines is how the immune system is exposed to the spike, or the antigen. Conventional vaccines contain the antigen itself. Now compare this to genetic vaccines:
[Paul A. Offit, MD:] You can take just really to the genetic material, either as messenger RNA or DNA, that then codes for that spike protein. So the person makes the protein. You're not giving them the protein. You're giving them the genetic material that then instructs them how to make that spike protein, to which they make an antibody response that hopefully is protective.
Two types of genetic vaccines are being investigated for COVID-19: mRNA and DNA. mRNA needs to reach the cytoplasm of host cells, while DNA needs to enter the nucleus. Then this genetic material gets taken up by the cell's machinery, and the cell expresses the spike protein. These spike proteins are then recognized by the immune system, hopefully stimulating a protective response.
These two candidates in the Warp Speed portfolio are mRNA vaccines. This one was developed by Moderna and the NIH, and was the first candidate to enter clinical trials in the US, with this one from Pfizer and BioNTech following not long after. Naked mRNA cannot easily cross cell membranes passively, and it's very susceptible to degradation. So in both of those vaccines, the mRNA coding for the spike is encased in small carrier molecules called lipid nanoparticles. Both of these candidates are currently in Phase 3 trials.
Now let's look at viral vector vaccines.
The basic idea is that you take another virus and replace its genetic payload with the sequence coding for the antigen, in this case the spike protein. The goal is to induce immunity against the target antigen--the added genetic cargo. But these vaccines may also induce immunity to the vector itself. The viruses used as vectors are attenuated, or weakened, so they cannot cause disease. A lot of different viruses have been developed as vectors, and they can be broadly categorized into two buckets: replication-defective and replication-competent.
Let's start with replication-defective vectors. A very popular choice among the potential COVID-19 vaccines is adenoviruses, like these two candidates, which are both in phase 3 clinical trials. Adenoviruses are common pathogens that typically cause mild cold or flu-like symptoms. This candidate, which was developed by the University of Oxford and AstraZeneca, uses a chimpanzee adenovirus 5, while this candidate from Johnson & Johnson, uses a human adenovirus 26. In both vaccines the adenovirus vector carries the DNA coding for the spike to the host cells, but it doesn't display it on its surface. Once the virus infects a host cell, it delivers the DNA to the nucleus; the cell's machinery then expresses the spike using this DNA, similarly to what we saw with genetic vaccines. And because these adenovirus vectors are replication-defective, after the virus infects a cell, no more viruses are produced.
Now let's take a look at replication-competent virus vectors. This Warp Speed vaccine that's being developed by Merck in partnership with IAVI is an example; it uses recombinant vesicular stomatitis virus. In humans, wild-type VSV is usually asymptomatic or causes a mild flu-like illness. The researchers replaced part of its RNA sequence with RNA coding for the spike. Unlike the adenoviruses, this rVSV vector does display the spike on its surface. After the rVSV infects a host cell, again the cell's machinery expresses the spike; but because rVSV is replication competent, this platform mimics a real viral attack more closely.
This is the same platform that Merck used to develop a vaccine for Ebola, which was approved by the FDA last year. But so far that Ebola vaccine is the only viral vector vaccine that has gotten FDA approval. Adenovirus vectors, which are much further ahead in COVID-19 trials, have never been used in an FDA-approved vaccine, and there are likewise no FDA-approved vaccines that use DNA or mRNA platforms.
So despite the investment in these approaches, and the media attention they've been getting, it's far from certain they will curb COVID-19.
[Paul A. Offit, MD:] I think the reason that you hear the most about the mRNA vaccine or the DNA vaccine or these replication-defective adenovirus vaccines is because they're the easiest to make. So I think that's why you hear about them first, but I just would want to warn people that, you know, what you want is you want the best and safest vaccine, which may not necessarily be the first vaccines.
And the only way to find out is through rigorous trials. Before COVID-19 hit, these platforms were extensively studied in animal models, and some candidates were tested in phase 1 and 2 trials, but until now phase 3 data has been lacking.
[Paul A. Offit, MD:] This is the -- if the proof is in the pudding, the pudding is a phase three trial, a large, prospective, placebo-controlled, safety and efficacy trial.
And platforms do not save time in clinical trials. No matter the approach, rigorous safety and efficacy testing is required. The safety standard for vaccines is very high compared to other interventions, because vaccines are potentially given to millions of healthy people.
If the phase 3 trials are done correctly, there will be enough data about both safety and efficacy in diverse demographic groups to allow health officials, doctors and individuals to make informed decisions. Until that data has been adequately analyzed, it's too early to say which approaches, either novel or conventional, are the safest and most effective.
A handful of vaccines are already in phase 3 trials, so some data will be available soon; and at that point--not before--we might find out if these next-generation platforms have lived up to their potential for combating emerging infectious diseases.
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