Here's What We Know About COVID-19 Vaccines

There are more than 200 COVID-19 vaccines in development, all designed to destroy a common enemy: SARS-CoV-2, the pathogen involved with the COVID-19 infection that has killed more than 700,000 people globally.

About two dozen vaccine candidates are currently being tested in clinical trials. Although nearly all of the frontrunner candidates have demonstrated some form of immune response in early studies, many trials measured this response with different tests, making it difficult to compare their findings directly. Moreover, the science behind many of these candidates is novel and none have been shown to generate a lasting immune response that protects against the virus in a final-stage trial.

Whether newer technologies -- like Moderna and Pfizer's mRNA vaccines, or CanSino and AstraZeneca's adenovirus vector vaccines -- will produce a more robust response than traditional vaccine technologies remains unclear.

All eyes are on the finish line to see which candidate pulls ahead in the vaccine race. But some may end up having better outcomes for certain populations, and multiple candidates may be approved to meet the high demand.

And "race" is an imperfect metaphor.

"We are thinking there is going to be one winner and it's a race to the end," said Naor Bar-Zeev, PhD, of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health. "You're going to want multiple winners. We want more than one to cross the finish line."

Nucleic Acid Vaccines

The mRNA candidates are exciting because they are pushing the envelope on vaccine research, and no vaccines of this kind have been licensed before, Bar-Zeev said.

These candidates work through messenger RNA, instructing the recipient's own cells to produce the SARS-CoV-2 spike protein on their surfaces. The immune system then recognizes these cells as foreign and mounts an immune response.

"I can make the body produce surface protein without even giving the body the virus or any infectious material," Bar-Zeev told MedPage Today. "Instead of giving you the computer, I give you the operating system."

Moderna's product, mRNA-1273, co-developed with the National Institutes of Health, induced a stronger neutralizing antibody response in patients compared with people recovering from the disease, according to phase I findings published in the New England Journal of Medicine. This candidate was the first to begin a phase III trial in the U.S. last week.

Pfizer's and BioNTech's mRNA candidate, BNT-162, has also shown positive preliminary findings; they launched their own phase III trial last week, too. This candidate encodes an optimized version of the whole spike protein that could produce "more consistent responses across diverse populations and older adults," Pfizer said in a statement.

Beyond side effects like fatigue and chills, which many vaccine candidates have been associated with in early data, one risk with any vaccine that winds up ineffective is that they could actually enhance disease.

The process is called antibody-dependent enhancement (ADE), where a vaccine generates antibodies and binds the virus but does not neutralize it. These antibodies could then enhance viral entry into the cells and increase viral replication, said Sanjay Mishra, PhD, project manager of the COVID-19 and Cancer Consortium in Nashville, Tennessee.

This phenomenon has been linked to both dengue and respiratory syncytial virus, but the evidence is inconclusive on whether the coronavirus poses this risk.

"Poor-quality antibodies that bind a virus without neutralizing are one reason why the vaccine candidates often fail," Mishra told MedPage Today in an email. "Any ineffective vaccine, in theory, could cause ADE."

Authors of the NEJM paper on the Moderna product alluded to this phenomenon, and said this risk could theoretically be reduced because it induced both an antibody and a T-cell response.

For vaccinologists, mRNA vaccines are attractive because they can easily be adapted to other pathogens, said William Moss, executive director of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health.

"Because it's based on the mRNA of the spike protein, if another COVID emerges, or perhaps even an influenza or Ebola virus, it would be pretty easy to adapt across pathogens," Moss told MedPage Today. "You need to know the genetic sequence of that pathogen and you need to know which gene to target, but it's a very flexible technology."

Yet the concept remains unproven for real-world vaccines. In one clinical trial examining an RNA vaccine for rabies, the response was "less than anticipated" compared to what was shown in preclinical studies, Bar-Zeev said.

From a practical standpoint, mRNA vaccines are unstable and must be kept at -80°C or else they degrade rapidly. (In contrast, standard inactivated vaccines need to be kept at around 5°C, which can be accomplished by a standard refrigerator.)

On the other hand, because these novel vaccines do not need to be manipulated in cell cultures, they could be mass-produced more easily than standard vaccines.

"We need a mechanism that can be scaled up quickly," Bar-Zeev said. "One difference with existing platforms is, they are not that easy to produce on a huge scale."

Similar to the RNA vaccines, one candidate from Inovio Pharmaceuticals uses DNA to provoke an immune response. Once inside a cell, the vaccine's DNA plasmids prompt the cell to produce the desired antigen and ultimately induce an immune response.

However, the DNA vaccines are not as far along in development as some of the RNA candidates, though Inovio announced positive phase I data in late June. Some also require an electrical pulse device or hypertonic saline to be co-administered with the vaccine.

Adenovirus Vector Vaccines

Another novel candidate involves an adenovirus that cannot replicate, and thus cannot cause disease. Unlike the mRNA vaccines, this strategy uses the adenovirus as a vector to deliver the actual coronavirus spike protein to cells, "infecting" them, which in turn causes an immune response. But because they are replication-deficient, the infection ends there, Bar-Zeev said.

One advantage of this technology is that the adenovirus vector can deliver almost any protein or antigen to generate an immune response, meaning this technique could also potentially be used for future epidemics. Most recently, the strategy has been used to protect against the Ebola virus.

Because this technique "infects" the body, it generates an immune response across all arms of the immune system, including antibody immunity and T-cell mediated immunity.

However, one disadvantage is that cells can develop an anti-vector immunity to the adenovirus.

"If the recipient has pre-existing immunity to the adenovirus vector, then the immune system could attack the vector before it succeeds in delivering the COVID-19 moiety into the cell," Bar-Zeev said. "This would reduce its effectiveness."

That being said, one of the leading adenovirus vector vaccine candidates from the University of Oxford and AstraZeneca, which also showed positive findings in a phase I trial published in The Lancet, uses a chimpanzee adenovirus vaccine, ChAdOx1. Because this adenovirus is not widely known to humans, pre-existing immunity is not likely, Bar-Zeev said.

In parallel, CanSino is working on a human adenovirus vaccine, Ad5, and recently published data from a phase II trial in The Lancet. The product generated neutralizing antibodies and a T-cell response in the majority of participants. However, this human adenovirus may be more known among humans, especially among older adults, Bar-Zeev noted.

This pre-existing immunity could also pose a challenge if a second dose is necessary. It's possible that a second dose would be less effective since the first dose induced anti-vector immunity, along with COVID-19 immunity, Bar-Zeev said.

Moss pointed out, however, that a single injection protocol appeared to be effective in both the human and chimpanzee adenovirus trials.

Tried and True Candidates

Because of the novelty of these platforms, the necessary supply chains and production capabilities are not fully in place like they are for traditional vaccine candidates. Nevertheless, manufacturers are promising that millions, even billions of doses will be available by 2021.

Developers are also working on live attenuated vaccines and inactivated vaccines, two traditional methods that have been used for smallpox and polio vaccines, respectively.

"These types of methods have been around for almost a century," Moss said. "These are tried and true."

Bharat Biotech and Sinovac Biotech in India are working on a live attenuated product called COVAXIN, and Sinopharm is currently conducting a phase III trial of an inactivated virus vaccine against SARS-CoV-2 in the United Arab Emirates.

Another now-conventional vaccine technology uses recombinant viral protein subunits as the immunity-provoking component. This week, Novavax announced positive findings from a phase I trial involving such a product. Vaccine giants Sanofi and GlaxoSmithKline are also collaborating on a spike protein subunit vaccine. Although it has not yet entered human studies, their product is the only one using proven technologies to be included in the U.S. government's "Operation Warp Speed" development and distribution program.

Whether vaccines with novel technologies will gain approval before the more traditional candidates will depend on how they perform in the clinical trials underway.

"The proof will have to be in the pudding," Bar-Zeev said. "Even if we are seeing neutralizing antibodies in early phase trials, we don't know how high your antibody levels have to be in order to protect you from infection."

Pfizer said it's on track to seek regulatory review as early as October of this year. The Pink Sheet reported Wednesday that plans are in the works for an Oct. 22 FDA vaccines advisory committee meeting. The agency has not publicly announced a meeting, however, and an FDA spokesperson declined to confirm or deny it.

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