The COVID-19 Vaccine Quest

The COVID-19 Vaccine Quest: A Unique Experiment in Both Immunology & Public Health

Th i s pa s t ja n ua r y c o l l a b o r a t i n g

scientists in Beijing, Wuhan and Jinan,

China identified the third severe acute respiratory virus affecting humans, SARS/CoV-2* (1) after an outbreak of such a disease had occurred in Wuhan a month before. Five days later another team in China published the virus’ RNA code (2) and within weeks, one U.S. company had designed a vaccine candidate based on this information. I open this article on this point in the context of concerns that U.S. science is vulnerable to illegal exploitation by China, as indeed has been confirmed in certain cases. But with SARS/CoV-2, the Chinese infectious disease physicians and virologists operated with astonishing speed and complete openness.

The vaccine developments have been and are now moving very rapidly, and with ongoing shifts in testing strategies and anticipated approval and deployment timelines. This article was finalized on October 26.

Two hundred and thirteen COVID-19 vaccines are in development and a dozen are already in Phase 3 trials. Readers wishing more details are referred to an excellent database maintained by the Milken Institute: milkeninstitute.org > COVID-19-tracker.

To adjust Senator Howard Baker’s famous Watergate remark from the past to future verb tense: “What will we know and when will we know it?”

the four vaccine concepts

Most of the COVID-19 vaccines in development are “conventional” in that they deploy, in one format or

*The coronavirus that is the infectious agent is termed SARS/CoV-2 and the condition is termed Covid-19 (for “Coronavirus disease 2019”). Here, either term is used depending on whether the virus or the infection is being discussed.

another, a particular protein that resides in the outer shell of the virus to hopefully trigger a subject’s immune system to make an antibody response. Although there are numerous proteins in the SARS/CoV-2 virus that could be tried in this approach, the “poster child” is one that constitutes the “spikes” on the coat that gives this clade of respiratory viruses its “crown”- based name. This protein has been purified and injected into animals to see if they produce antibodies against the protein. They do of course but how successful this approach will be as a protective vaccine is not yet clear.

In one variation of this approach, many copies of the spike protein are assembled in the lab into a “virus-like particle” (VLP), with the idea that these proteins will thus be “seen” by the animal or human subject’s immune system as more closely resembling how these proteins appear on the actual virus. When positioned in a VLP, the spike protein adopts the same shape and orientation it has in the actual coronavirus, whereas in the vaccines based on individual, free-floating copies of this protein it may adopt alternative shapes that are not as stimulatory to the immune system. One of the pioneers of this concept is Trudy Morrison, a professor at UMass Medical School, who has validated this vaccine concept for a different human respiratory virus and is now applying it to SARS/CoV-2.

Another coronavirus vaccine concept is to use the SARS/CoV-2 spike protein itself (vide supra). Hamster cells can be genetically engineered to make it and it can then be easily harvested and tested as a vaccine. In this strategy the protein is often combined with another entity to hopefully boost its antibody-generating activity.

Yet another strategy is to insert the genetic code of the spike protein into a human cold/respiratory virus called adenovirus. The track record of this type of vaccine for other viruses is not encouraging but each new virus on the scene is a distinct entity and we cannot predict how any given vaccine strategy tried before will or will not be promising.

A fourth type of coronavirus vaccine in development is based on using the genetic code of the spike protein not as DNA, as in the adenovirus-based vectors mentioned above, but in the form of the so-called messenger RNA that causes the protein to be made in the protein synthetic factories of the infected cell. In this strategy, the messenger RNA that codes for the spike protein is put into a capsule and then injected into subjects. It then causes the cells it reaches to make the spike protein which is then released into the bloodstream to thus elicit an antibody response.

There is yet a fifth vaccine strategy- using the virus itself. But the consensus of respiratory virus disease experts is that vaccines based or live or attenuated SARS/COV-2 virus should not be pursued.

putting things into perspective

There are no solid bets with respect to the vaccine strategies described above although various experts “lean in” on one vs. others. I take a circumspect view because the history of vaccines is littered with failures, many of these involving such detailed knowledge of the virus that success seemed assured at the time. But knowing the virus in laboratory studies is one thing and knowing its lifestyle in the infected host is another. A good example is polio, where both the virus and the disease were well understood and yet the vaccine breakthrough came out of nowhere. There had been a widely accepted belief that the polio virus could not grow in non-nervous system tissue and thus could not be amplified at vaccine production

scale, because nerve tissue cannot be readily expanded in cell culture. But this turned out to be wrong and it resulted in vaccines, and a Nobel Prize (1).

When we think about the advent of a vaccine, we of course mean a highly protective one and which can be administered very broadly as to production scale and breadth of distribution. By mid-late November the levels of coronavirus antibodies elicited in one or more of the ongoing Phase 3 trials may be known, not from the completed trials but from early indications that carry a degree of statistical meaning. But at such a time we will not know the degree of immunity as these are not challenge trials, i.e. ones in which vaccinated subjects are given the virus. Two such trials have been conducted in monkeys, one with an adenovirus-based vaccine and the other the messenger RNA type. Both demonstrated significant degrees of protection and this is, to me, one of the most encouraging signposts so far. In late September the British government announced it was considering the launch of a human challenge trial. But even if challenge trials were to be conducted in the coming months, the duration of immunity would need to be determined. The pediatric measles-mumps-rubella vaccine typically provides enduring immunity, often for life. No respiratory disease virus vaccine has ever achieved this.

Even if we are optimistic enough to think the early data on the vaccines now in Phase 3 trials will be encouraging, on October 6 the FDA issued updated safety standards requiring subjects to be followed for two months prior the companies seeking emergency approval. Thus, it is likely such approvals would not be granted until mid-late January.

There is another issue: mutation. 5,000 different single-mutation versions of SARS/CoV-2 were compiled in a report posted by a team of U.S. scientists in September, and a larger number were published earlier in a British study. Most of these were inconsequential as regards infectivity although one was associated with increased severity of infection. The various antibody strategies outlined earlier in this article are likely to have varying degrees of “breadth”, i.e. the extent to which a given vaccine elicits antibodies directed against different regions of the virus’ antigenic protein. Clearly, the more the better given the observed mutation rate. One particular vaccine approach involves so-called monoclonal antibodies against the virus’ spike protein but used as a combination (“cocktail”) of several for this reason.

Other biological parameters are in the picture. One is a phenomenon called “antibody dependent enhancement”, or ADE, in which the antibodies in a vaccine paradoxically enhance the virus’ ability to

enter the cells of subject. All the vaccine developers are watching signs of ADE. Another factor is the degree of human variation with respect to genes that elevate or reduce either the propensity for SARS/CoV-2 infection, or the severity of the disease. A private-government consortium in England is carrying out such a “genomics” study on 15,000 subjects who experienced mild COVID-19 disease vs. 20,000 who had intense symptoms.

Yet another parameter, perhaps the most important and yet somewhat vexing, is “herd immunity”, defined as the state at which the number of immune individuals in a given population has reached a level in which further transmission is negligible or even absent, due to an insufficiency of vulnerable individuals. Herd immunity is why we are still around, descendants of the survivors of even the most horrific plagues in history, eras that were of course pre-vaccines. It is thought that for most viral diseases herd immunity is attained when somewhere around 70% of the population is immune, either from vaccination or natural infection. But some infectious disease epidemiologists have come out with lower estimates in the case of COVID-19, in the range of 45-50%. This is based on modeling that takes into consideration the value called R0, which is the estimated number of people that become infected by a given individual. Variables such as the relative frequency of young vs. older people in a given population, or the density of people (urban, rural), have been meticulously weighed in these models using epidemiological data for COVID-19 already in hand. For example, a study conducted in Mumbai, India found that 51-58% of people living in the highest density areas of poverty had SARS/CoV-2 antibodies vs. only 11-17% in the more affluent areas. Two unpublished studies of SARS/CoV-2 natural immunity have yielded encouraging results. In one, patients having had mild cases displayed antibodies to the virus for at least three months and in some cases the antibody levels increased during this period, indicating the subjects’ immune systems were in an amplification state. The second study included mild vs. severe cases, as well as asymptomatic infected individuals. The more severe cases displayed higher levels of antibody but in all three groups, the duration of antibodies was two-three months. Of course, how such levels and duration would play out as to approaching herd immunity would depend on the population-based variables mentioned above. One other finding of interest in the second study was that the age and sex of the subjects played a lesser role in the antibody response than the severity of symptoms.

Production and distribution issues loom large. The capital investments being made in vaccine discovery and validation are indeed substantial but as we have all read in the media, there are questions about the cost and feasibility of shipping many of these various vaccines given current refrigerated transport modalities, both as sheer capacity and sustained ultra-low temperatures (in some cases requiring -110 o F). Air shipment will be extensive given that the production of any vaccine will be at one or only a few sites around the world and dry ice sublimation on-flight is a serious concern for cargo airlines and must be controlled, at substantial cost, to say nothing of the energy balance sheet for manufacturing amounts of dry ice never before achieved. The anticipated levels of glass and/or plastic manufacturing for vials and syringes has been predicted to stretch current world capacity. (As a 7-year old boy I toured the Corning Glass plant in southern New York and marveled at the masters making “Steuben glass” of scintillating beauty. The descendent

of that company is among the contractors for the COVID-19 vaccine effort).

Finally, we must face yet another challenge and this is the disturbing degree of vaccine skepticism that abounds in many parts the world. It turns out the roots of this are more complex than many might assume and although they parallel to some degree an anti-science stance or science illiteracy (4), in some quarters the skepticism is more focal and less irrational, e.g. a suspicion of corner-cutting by pharmaceutical companies. These are formidable issues that could reduce the levels of vaccination. Nonetheless, it is likely that eventually (I suspect by the fall of 2021), there will be sufficiently potent vaccines in amounts for widespread deployment with willing subjects that these levels of immunity together with that from natural infections will combine effectively.

The science of SARS/CoV-2 is still a frontier, and we may have surprises that are setbacks. Or we may see successes that mirror what vaccinology has done in the past at its most heroic moments (5,6). I predict the latter. +

disclosure: I own stock in one company that is working on a COVID-19 vaccine. For this reason, I have not mentioned any companies in this article. The categories of vaccines described, and the companies working on them, can be readily found on the Milken Institute site.

references:

1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. New Engl. J. Med. 382: 727-733, 2020.

2. Lu, R. et al. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet 395: 565-574, 2020.

3. Pederson, T. Turning on a dime: the 75th anniversary of America’s march against polio. The FASEB J. 27:2533-2535,2013.

4. Pederson, T. How Americans see science: what’s in a poll? FASEB J. 34:14059-14060, 2020.

5. Kinch, M. “Between Hope and Fear: A History of Vaccines and Human Immunity”. 2018, Pegasus.

6. Wadman, M. “The Vaccine Race: Science, Politics and the Human Costs of Defeating Disease”. 2018, Penguin Books.

Thoru Pederson, PhD is Arnett Professor of Cell Biology, Professor of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School. E-mail: thoru.pederson@umassmed.edu