COVID-19 Vaccines: Will Next-gen Platforms Be First?

Feeling a little overwhelmed by all the vaccine news on the different COVID-19 vaccines? You are not alone: 140 vaccines are in preclinical trials, about 30 are in human trials, and 2 have been approved, 1 in China that will only be given to members of their military and 1 in Russia. Neither of these has undergone the testing needed to assure a safe, effective vaccine.

I am going to try to simplify it for you and talk about the advantages and disadvantages of the 8 different vaccine development platforms being used.

Existing development platforms

Four of the 8 platforms are currently used to make vaccines we use every day in my office. Those 4, however, are behind in the development timeline as compared to the COVID-19 vaccines being researched using 4 next-generation vaccine platforms. Key advantages to the 4 original models are that existing manufacturing capacity can be used and that, if produced, the final product will be generally a more temperature-stable one.

The 4 existing development models that have COVID-19 vaccine candidates being researched:

• Whole cell inactive eg, polio shot
• Live attenuated eg, MMR vaccine
• Protein subunit eg, flu vaccine
• VLP (virus like particle) eg, Gardasil

A concern with the live attenuated vaccine would be reversion through mutation to the wild virus that is rarely seen with our live polio vaccine.

Novel development platforms

The 4 novel, or "next generation" vaccine platforms are ahead in the race since all are based on the viral genetic sequence of the SARS-CoV2 virus which was discovered very early in the pandemic. In general, these vaccines may be easier to make and don't need live virus in the production process, but will be more temperature-unstable, so shipping and storage will need to be carefully monitored to avoid vaccine inactivation before administration.

The 4 next generation development models that have COVID-19 vaccine candidates being researched:

• Viral vector eg, Ebola vaccine
• DNA-based None licensed
• RNA-based None licensed
• Antigen-presenting cells None licensed

All vaccine development involves finding an antigen(s) that is recognizable by the immune system, leads to the production of antibodies that work to prevent infection, and is not so reactogenic as to preclude its use. Ideally, memory T and B cells will be stimulated resulting in long term immunity.

Different antigens produce different levels of antibodies and can trigger different types of immune response (T cell, B cell, and cell-mediated). So:

Step 1: Find the right antigen.

Step 2: Get the antigen to be “seen” by the human immune system

Viral vector platform

The viral vector approach takes an infectious human virus, adenovirus is one of several being used, and genetically modifies it to produce the COVID-19 antigen and perhaps also to attenuate the viral vector. The carrier virus infects human cells, injects its genome containing the gene coding for the COVID-19 antigen, and the human cell makes the antigen.

The vector can be replicating, meaning new viral carrier particles (essentially, new vaccine) are produced that spread to new cells. Non-replicating viral vectors also are in development. Viral vector vaccines seem to be very immunogenic and most likely only one dose will be required, unlike most of the others for which 2 doses will be needed.

Drawbacks with the viral vector vaccine include the possibility of side effects and that someone with a recent infection with a virus in the vector family may have an immune response that destroys the viral vector before it can infect enough cells.

That said, viral vector vaccine trials have a good track record with other emerging viruses, Ebola being one.

DNA- and RNA-based platforms

The DNA- and RNA-based vaccines need to get those snippets of viral genome that code for a COVID-19 antigen into human cells so they can make the viral antigen that stimulates the immune response. An American company working on a DNA-based vaccine uses a hand-held electrical device to drive plasmids containing the COVID-19 DNA (but just the bit that codes for a spike protein, so no risk of infection) into human cells. The electrical jolt does add some pain in addition to the shot. RNA-based vaccines use a lipid nanoparticle that is taken up by cells. The mRNA vaccines seem to produce more antigen per cell but are much more temperature unstable as compared to DNA vaccines.

The last new vaccine platform uses artificial antigen presenting cells (APCs), pre-loaded with a COVID-19 antigen. The APCs then present these antigens to T and B calls that cannot detect the free or soluble antigen on their own. In theory, this vaccine should work more quickly since the antigen doesn't need to be produced, then taken up by the antigen presenting cells that then have to present it to natural APCs. The injected artificial APCs can bypass these preliminary steps, shortening the time from vaccination to protection that is normally about a 2-week process. Vaccines using modified, immortalized APCs that effectively mimic human APCs are in clinical trials.

Which vaccine will prevail?

Which vaccine candidate will win out? I suspect it will be whichever one gets to market first which is most likely going to be one made using one of the newer technologies. Sadly, I can already hear the howls of protest from antivaxxers: “Genetic engineering,” “Messing with the human genome,” “Untested, never before used, rushed to the market” and “Aborted children's cell line used in manufacture of some COVID vaccines.” Some truth exists in these claims but I suspect Dr. Fauci will be one of the first in line to receive it and I will be right behind him.

COVID-19 herd immunity

Our only way out of this pandemic crisis will be to achieve herd immunity which I fear will be difficult in the United States given the number of Americans already refusing to get this “experimental” vaccine. A recent Associated Press poll showed only half of Americans plan to get the vaccine.

My recommendation to them: Talk to a family member of one of the 163 000 Americans who has died and see what their thoughts on a vaccine are.

Times have changed since the 1950's when families waited in lines for hours to get the new polio vaccine. I was one of them.

Resources and additional reading

Regulatory Affairs Professional Society COVID-19 Vaccine Tracker

Site is tracking/updating all the COVID-19 vaccines in trials

National Vaccine Information Center: The Vaccine Reaction

Article discusses the use of electricity to drive a DNA-based vaccine into a cell. (Benjamin Franklin would be proud.)

Next-generation vaccine platforms for COVID-19. Nature Materials.

A summary that goes into more detail about the different platforms with their advantages nd disadvantages.

_________________________________________________________________________________

For more COVID-19 coverage for primary care, visit our COVID-19 Resource Page.

For the most recent update on all-things COVID-19 vaccine-related, https://endpts.com/28-players-are-in-or-about-to-jump-in-to-the-race-to-a-global-multibillion-dollar-market-for-a-covid-19-vaccine-heres-how-they-rank-so-far/