There are more than two hundred COVID-19 vaccines in development, all designed to destroy a common enemy: SARS-CoV-2, the pathogen involved in the COVID-19 infection that has killed more than 700,000 people worldwide.
Approximately two dozen vaccine applicants are recently being tested in clinical trials. Although almost all lead applicants demonstrated some form of immune reaction in early studies, many trials measured this reaction with other tests, making it difficult to directly compare their results. In addition, the science of many of these applicants is new and none have been found to generate a lasting immune reaction that protects the virus in a final phase of testing.
It is known whether new technologies, such as Modern and Pfizer mNA vaccines or adenovirus vaccines CanSino and AstraZeneca, will produce a physically more powerful reaction than classic vaccine technologies.
All eyes are on the final line to see which candidate wins in the vaccine race. But some would possibly end up having greater effects for certain populations, and several applicants would possibly be approved to meet the main demand.
And “race” is an imperfect metaphor.
“We believe there will be a 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 need several winners. We need more than one to cross the baseline.”
Nuclear acid vaccines
MRNA applicants are excited because they are overcoming the barriers of vaccine research and no vaccine of this type has been approved before, Bar-Zeev said.
These applicants paint messenger RNA, asking the receptor cells themselves to produce the complex SARS-CoV-2 protein on their surfaces. The immune formula then recognizes these cells as foreign and develops an immune response.
“I can make the frame produce surface proteins even by giving it the virus or any other infectious material,” Bar-Zeev told MedPage Today. “Instead of giving you the computer, I’ll give you the operating system.”
Moderna’s product, mNR-1273, developed in conjunction with the National Institutes of Health, induced a more potent neutralizing antibody reaction in patients than in convalescent individuals, according to phase I effects published in the New England Journal of Medicine. This candidate is the first to start a Phase III trial in the United States last week.
Pfizer and BioNTech mNS candidate BNT-162 also showed positive initial results; they also submitted their own Phase III trial last week. This candidate encodes an optimized edition of all the complex protein that can produce “more consistent responses in varied and elderly populations,” Pfizer said in a statement.
Beyond the side effects such as fatigue and chills, to which many candidate vaccines have been linked in the early data, one threat with any vaccine that is useless is that it can worsen the disease.
The procedure is called antibody-dependent potention (AD), where a vaccine generates antibodies and binds to the virus but does not neutralize it. These antibodies can then have viral access to cells and develop viral replication, said Sanjay Mishra, PhD, COVID-19 allocation leader and Cancer Consortium in Nashville, Tennessee.
This phenomenon has been linked to dengue fever and respiratory syncytial virus, but there is no evidence of whether coronavirus presents this risk.
“Poor quality antibodies that bind to an un neutralized virus are one of the reasons vaccine applicants fail,” Mishra told MedPage Today in an email. “Any vaccine that is ineffective, in theory, can cause EAD.”
The authors of NEJM’s paper on the Modern product alluded to this phenomenon and stated that this threat can theoretically be reduced because it induces an antibody and T-cell response.
For vaccine specialists, mRN vaccines are because they can be seamlessly adapted to other pathogens, said William Moss, executive director of the International Center for Vaccine Access at the Johns Hopkins Bloomberg School of Public Health.
“Because it’s based on the mRN of the complex protein, if some other COVID, or even a flu or Ebola virus arises, it would be quite simple to adapt to all pathogens,” Moss told MedPage Today. “You want to know the genetic series of this pathogen and you want to know which target gene, but it’s a very flexible technology.”
However, the concept of real-world vaccines remains to be demonstrated. In a clinical trial that examined an RNA vaccine opposed to rabies, the reaction “below expectations” compared to what was shown in preclinical studies, Bar-Zeev said.
From a practical point of view, mNR vaccines are volatile and should be kept at -80 degrees Celsius or degraded rapidly. (On the other hand, popular inactivated vaccines should be maintained at about five degrees Celsius, which can be achieved with a popular refrigerator).)
On the other hand, since these new vaccines do not want to be treated in mobile crops, they may be mass-produced more easily than vaccines.
“We want a mechanism that can expand rapidly,” Bar-Zeev said. “One difference with existing platforms is that they are so simple to produce on a giant scale.”
Similar to RNA vaccines, an Inovio Pharmaceuticals candidate uses DNA to boost an immune response. Once inside a mobile, the DNA plasmids of the vaccine induce the mobile to produce the desired antigen and, in the end, induce an immune response.
However, DNA vaccines are not as complex in progression as some of the RNA candidates, Inovio announced a positive understanding of Phase I in late June. Some also require an electric pulse device or hypertonic saline to be co-administered with the vaccine.
Vector adenovirus vaccines
Another new candidate arrives at an adenovirus that cannot be replicated and cannot cause disease. Unlike mNR vaccines, this strategy uses adenovirus as a vector to supply the actual complex coronavirus protein to cells, which in turn causes an immune response. But because they are deficient in replication, the infection ends there, Bar-Zeev said.
One credit for this generation is that the adenovirus vector can supply almost any protein or antigen to generate an immune response, meaning that this strategy can also be used for long-term epidemics. More recently, the strategy has been used to oppose Ebola.
Because this “infects” the body, it generates an immune reaction in all arms of the immune system, adding antibody immunity and T-cell-mediated immunity.
However, one disadvantage is that cells would possibly expand anti-vector immunity against adenoviruses.
“If the receptor has pre-existing immunity opposite the adenovirus vector, then the immune formula can simply attack the vector before it succeeds in delivering the COVID-19 fragment into the cell,” Bar-Zeev said. “It would be their effectiveness.”
That said, one of the leading applicants for adenovirus vaccines from the University of Oxford and AstraZeneca, which also showed positive effects in a Phase I trial published in The Lancet, uses a vaccine opposed to chimpanzee adenovirus, ChAdOx1. Because this adenovirus is widely known to humans, pre-existing immunity is unlikely, Bar-Zeev said.
At the same time, CanSino is running with a human adenovirus vaccine, Ad5, and recently published knowledge of a phase II trial in The Lancet. The product generated neutralizing antibodies and T-cell reaction in most participants. However, this human adenovirus is possibly better known in humans, especially in older adults, Bar-Zeev noted.
This pre-existing immunity can also be a challenge if a momentary dose is required. It is conceivable that a momentary dose is less effective since anti-vector immunity induced through the first dose, with COVID-19 Immunity, Bar-Zeev said.
Moss noted, however, that an injection protocol for single people gave the impression of being effective in adenovirus trials in humans and chimpanzees.
Proven and true candidates
Due to the novelty of these platforms, the required source chains and production capacity are not fully in position as with classical candidate vaccines. However, brands promise that millions or even billions of doses will be obtained by 2021.
Developers are also using attenuated and inactivated vaccines, two classic strategies that have been used respectively for smallpox and polio vaccines.
“These strategies have been around for almost a century,” Moss said. “These have proven their worth.”
Bharat Biotech and Sinovac Biotech in India are using a dimmed product called COVAXIN, and Sinopharm is recently conducting a Phase III trial of an inactivated virus vaccine against SARS-CoV-2 in the United Arab Emirates.
Another generation of vaccines now traditional uses recombinant viral protein subunits as a immunity-motivating component. This week, Novavax announced the positive effects of a Phase I trial involving such a product. Vaccine giants Sanofi and GlaxoSmithKline are also participating in a protein subunit vaccine. Although it has not yet entered human studies, its product is the only one that uses displayed technologies that will be included in the U.S. government’s “Operation Warp Speed” distribution and progression program.
If vaccines with new technologies will be approved before the maximum classical applicants will have their functionality in ongoing clinical trials.
“The evidence will have to be in the pudding, ” said Bar-Zeev. “Even though we see neutralizing antibodies in trials in the first phase, we don’t know how high their antibody levels will have to be to protect it from infection.”
Pfizer said he was on track to seek a regulatory review starting in October of this year. Pink Sheet reported Wednesday that plans are being prepared for an assembly of the FDA’s Vaccine Advisory Committee on October 22. However, the firm has not publicly announced an assembly and an FDA spokesperson has refused to verify or deny it.
Elizabeth Hlavinka covers clinical news and research articles for MedPage Today. It also produces episodes for the Anamnesis podcast. Follow
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