During the past year, many thousands of articles and commentaries have been published on almost every imaginable aspect of the SARS-Cov-2 virus and the COVID-19 pandemic it has caused. They have appeared online, in journals, on preprint servers, in newspapers, and on Facebook and Twitter, to say nothing of local electronic bulletin boards. TV news programs continue to feature prominently the latest developments and statistics.
As the rollout of COVID-19 vaccines has progressed throughout the country, a prominent issue is vaccine hesitancy – that is, the uncertainty or unwillingness of a significant fraction of the population to take the vaccine. Recent polling suggests that about 31% of Americans are undecided, while about 20% remain at least somewhat reluctant. However, receptiveness seems to be increasing as frontline health care personnel, essential workers, and older people are vaccinated, and stories circulate about ineligible people devising ways to jump the queue.
Most of the reasons people cite for hesitancy about the COVID-19 vaccines concern the speed at which they were developed or the “novelty” of the first two that were authorized by the U.S. Food and Drug Administration for emergency use – namely, the “messenger RNA-derived” vaccines produced by Pfizer and its partner BioNTech and Moderna respectively. The points below will, I hope, dispel some of those reservations, and encourage vaccination and other precautionary measures.
Coronavirus vaccines are not new. Coronavirus infections are common in companion animals and economically important livestock and vaccines to prevent these infections have been widely employed in veterinary medicine for many years. They have been administered to dogs, cattle, pigs, and poultry. (The animal coronaviruses are sufficiently different from SARS-CoV-2 that the veterinary vaccines would not prevent COVID-19 in humans.) The more than a dozen veterinary vaccines licensed in North America have been developed with an array of technologies and platforms, including genetic engineering – but none, as yet, with the messenger RNA technology (mRNA) used for the Pfizer-BioNTech and Moderna vaccines. However, see the following paragraph.
The “novel,” messenger RNA technology to make the first two approved COVID-19 vaccines isn’t fundamentally new. Many reporters and commentators have dutifully noted that vaccines have traditionally been composed of killed or attenuated (weakened) viruses so that they can elicit an immune response without causing disease. In contrast, the Pfizer-BioNTech and Moderna COVID-19 vaccines are made with a genetic engineering technology called messenger RNA (mRNA), which acts in a novel way. When injected into a person’s muscle, the mRNA is read by the cells’ protein-synthesizing machinery and gives rise to numerous copies of a version of the SARS-CoV-2 virus “spike protein,” which is on the surface of the virus and plays a key role in attaching to the host’s cells. Those proteins elicit an immune response, so that if the person who has been injected later comes into contact with the infectious SARS-CoV-2 virus, the body’s antibodies and immune cells are prepared to neutralize it.
However, there’s a link missing in that narrative about the continuum from traditional vaccine development techniques to mRNA – namely, decades-old availability of “subunit vaccines,” which are conceptually similar to using mRNA for vaccines. A good example is Merck’s hepatitis B vaccine Recombivax, which has been around for more than 30 years. What is injected and stimulates the immune response in that case is a non-infectious viral protein that is synthesized in genetically engineered baker’s yeast grown in huge fermentation vats. The protein, which is analogous to the coronavirus’ spike protein, is then purified and used as the active substance in the vaccine.
A similar example is GlaxoSmithKline’s shingles vaccine Shingrix, which contains a glycoprotein (a protein linked to a carbohydrate) that is a component of the varicella zoster virus, and which is synthesized in genetically engineered Chinese hamster ovary cells.
There is also a COVID-19 vaccine using this technology being developed by Maryland-based Novavax. It contains proteins produced in genetically engineered insect cells that resemble the “spike” proteins found on the surface of the coronavirus, and which elicit an immune response after being injected.
The Merck, GlaxoSmithKline, and Novavax subunit vaccines are something of an intermediate approach between the killed or attenuated vaccines and the mRNA ones because the antigen injected is a protein, whereas the mRNA vaccines cause a protein to be synthesized in the muscles of the vaccine recipient after injection. An understanding of this continuum of approaches to vaccination should help to demystify COVID-19 vaccines for the considerable number of people who may be hesitant about taking a “novel” vaccine that was rapidly developed and approved.
The reported differences in efficacy among the various approved vaccines must be considered in context. We are at a good news-bad news situation with respect to COVID-19 vaccines. The positive news is that on Feb. 27, the FDA granted emergency use authorization to Johnson & Johnson’s single-dose coronavirus vaccine, providing the medical community with a new and more versatile option that requires only a single shot to induce immunity, and that has less stringent storage requirements than those for the other two approved vaccines.
However, the clinical trial data suggest that the J&J vaccine has lower efficacy, leading some public health experts and government officials to worry that it will be viewed by the public as substandard compared to the other vaccines. The Johnson & Johnson efficacy rate is 66% overall and 72% in the United States in preventing moderate to severe cases of COVID-19, while the two-shot regimens of the Pfizer-BioNTech and Moderna vaccines are about 95% effective at preventing symptomatic infections.
However, those numbers are not directly comparable, and context is critical to understanding the significance of these numbers. First, all three of the approved vaccines have been shown to be fully effective in protecting against the most important outcomes of COVID-19 – hospitalizations and death. Also, the two earlier vaccines were tested months before the emergence of “variants of concern,” including one first detected in South Africa that appears to affect the efficacy of the vaccines, so the results are not an “apples to apples” comparison. People should not be hesitant to get the J&J vaccine, and should take whichever vaccine is offered to them.
The appearance of these variants of concern is consequential. As World Health Organization epidemiologist Dr. Maria Van Kerkhove has pointed out, “The more of this virus circulates [because of greater transmissibility], the more opportunity it will have to change” to something worse. She concluded, “We’re playing a very dangerous game here.” Thus, the more safe and effective vaccine that becomes available and can be administered, the better.
When somebody tells you that we shouldn’t worry about an illness “with a survival rate of 99.99%,” or that “herd immunity” from natural infections will stop the pandemic, you’re about to be misled. First of all, a conservative estimate of the death rate is not 0.1% (which would correspond to a survival rate of 99.9%), but probably well above 0.2%. That might not sound like a lot, but when applied to a huge number of cases, it can be catastrophic – as it has been: COVID-19 has killed 515,000 Americans, been diagnosed in about 30 million, and certainly infected more than that number.
Second, deaths and death rates are far from the whole story. In many people, symptoms of COVID-19 persist long after “recovery” from the acute illness, even in those who have experienced only mild illness. A study by researchers at the University of Washington found that about a third of COVID-19 patients who were never sick enough to require hospitalization continue to complain as long as nine months later of symptoms like fatigue, loss of smell or taste and “brain fog.” Similarly, according to the Mayo Clinic, the most common persistent signs and symptoms are fatigue, shortness of breath, cough, joint pain, and chest pain; and “the virus can damage the lungs, heart, and brain, which increases the risk of long-term health problems.”
Finally, “herd immunity,” the point at which a sufficiently large fraction of the population is immune to infection because of natural infection or vaccination and causes the pandemic to wane, is thought to be upward of 80% in the case of COVID-19. In the absence of vaccines, achieving herd immunity would, in a best case, require natural immunity following infection of more than 260 million Americans, which would result in an unimaginable death toll.
However, herd immunity via that route would likely be unattainable because of the appearance of the “variants of concern” mentioned above, some of which are sufficiently different from the early prevalent strains of SARS-CoV-2 that they can overcome the immunity of people who were infected with an earlier strain and reinfect them. Moreover, echoing Van Kerkhove’s observation above, the greater the number people who are infected with any strain of SARS-CoV-2, the more virus there is circulating, the more virus replication and mutations, and more opportunity for Darwinian evolution to select for variants that are more “fit” – that is, more transmissible, thereby extending or expanding the pandemic.
We have come a long way in understanding COVID-19, but much remains unknown. The scientific and medical communities in the public and private sectors will continue to produce important new products and knowledge so we can lessen the toll of this awful pandemic as much and as rapidly as possible. In the meantime, it is more important than ever to continue to take precautions – including widespread vaccination – to flatten the curve.
Henry I. Miller, a physician and molecular biologist, is a senior fellow at the Pacific Research Institute. A co-discoverer of a key enzyme in the influenza virus, he was the founding director of the FDA’s Office of Biotechnology. Follow him on Twitter: @henryimiller