November 4, 2020

We are in the midst of a pandemic of coronavirus which is producing significant morbidity and mortality around the globe. Transmission models assume that coronavirus infection produces immunity for at least a year. However, there appears to be only a limited pre-existing immunity to the SARS-CoV-2 (COVID-19) virus left by exposure to other coronaviruses, as judged by the rapid and sometimes explosive increase in cases. Our knowledge of the nature of the immune response to COVID-19 is limited and the scientific basis for a durable immunity to this virus is not well developed.

There is some information from human experimental infections that suggest protection after coronavirus infections for about 1-2 years. The coronaviruses used for these challenges were of low severity since the severe illness produced by this virus precludes its use for human experimentation. A recent article in Nature Communications, by Huang et al., reviewed 2452 abstracts and identified 491 manuscripts that provided a comprehensive overview of immunity to coronavirus. The important findings were as follows: the median time to detection of infection was 11 days with a range of 7–14 days. Most long-term studies found that immunity waned overtime and was typically detectable for about a year. However, some studies found immunity still present at three years post symptom onset. Antibodies were detectable longer after more severe illness. Other epidemic coronavirus–induced antibodies (MERS and SARS viruses) do not induce cross-reactive antibodies. But other serologic studies showed that with the four major endemic coronavirus strains, antibodies rose rapidly during childhood and remained high in adults. The first infection with any strain was at about five years of age, with a range of 2.5–11.2 years. This suggests that endemic immunity may have an impact on coronavirus infections acquired in the future, but the protection may be transient and its actual therapeutic value is unclear. Thus, we cannot count on previous coronavirus infections in our childhood or those acquired from our children when they went to school to protect us during the current pandemic. An effective vaccine that is widely distributed and used will be necessary if we are to produce a large enough population immunity to halt this pandemic. I have removed the word “herd” generally used in the public health literature to describe the per cent of immune individuals needed to halt transmission since it has become, strangely, controversial. This is a result of our turbulent political discussions, casual media misuse, and poor understanding of the definition generally. Sadly, the herd has been cancelled. Perhaps we can rehabilitate it later.

Population immunity is a basic concept in epidemiology and is a statistical estimate of what percent of a population must be immune in order to prevent the person-to-person transmission of a contagious disease. The calculation is relatively simple if one knows the R0  (pronounced R naught). This is the number of people that one infected person will go on to infect. If the R0 is less than 1, the epidemic will halt; if it is greater than 1, the epidemic will continue and the larger the number the more rapidly the epidemic will develop. Although there is a range for the R0 estimate, most authorities agree that the number 2.5 can be used for the calculation. The % of our population that must be immune to produce a herd immunity is:

 

% = 1-(1/R0) x 100

                                                            Using R0 = 2.5,

                                                            Then:

                                                                        % = 1-(1/2.5) = 1- (0.4)

                                                                        % = 0.6 x100  

 Or

                                                                        % = 60

This indicates that we must have a population immunity of about 60%. The number used in some reporting will vary depending upon the R0 chosen but it is clear that we must produce immunity in about half of our population and, probably half the world as well. This means the vaccine must be efficacious, widely distributed, and widely used. There must be no opting out of a vaccine campaign because to do so puts not only that person but all the rest of us in jeopardy.

There are about 170 vaccines in development around the world and several are close to final testing. Generally, tests are done in three phases: phase 1 is a small trial to determine safety of the vaccine; phase 2 is a somewhat larger trial to determine efficacy; if that phase is successful then a large, and longer, phase 3 trial is undertaken to show efficacy (and safety)in a larger population. The first two phases usually have test populations measured in hundreds or low thousands (ini phase 2) of people; phase 3 will have a population measured in larger thousands. As a result, vaccine development, - even after the laboratory actually has created a vaccine worth testing ,which can take many months as well - can take years to demonstrate efficacy of a degree that makes the product worth manufacturing.

The urgency of this pandemic has caused the United States to modify the usual vaccine testing regimens in which individual companies will test vaccines. We now have a parallel technology platform system with a large volunteer population that will allow a company to test its vaccine on part of the population and subsequent companies to test their vaccines on other parts of that same large population. This creates a parallel rather than a sequential process. It is this scheme, created at the National Institutes of Health, that may permit the United States to have a vaccine in a time period of many months rather than years.

In addition, the investment of $10.7 billion up front by the US government to support clinical trials and development effectively eliminates commercial risk to the vaccine companies. The infrastructure for coronavirus vaccine development program and the FDA plans to verify safety and efficacy both are quite good. They are a major advance in vaccine development and are due to the rapid and capable response of medicine, science, and public health experts to the pandemic. Unfortunately, these quiet and substantial advances do not provide the histrionic and melodramatic theater desired by the media and we are not told about them. Progress now depends upon the efficacy and safety of the vaccines submitted for approval.

The nature of these vaccine candidates varies, but they fall into the general headings of genetic and protein starting points. The former include messenger RNA that is modified and injected and then taken up by cells that begin to synthesize the protein it codes for. This serves as the immunological stimulus to create antibody. Moderna and BioNTech/Pfizer are using this method. AstraZeneca and Johnson&Johnson are using a modified adenovirus vector that, when injected, will enter cells and then begin to produce the coronavirus surface protein antigen it carries in its own DNA. Two other companies, Novavax and Sanofi/GSK are using a more standard, and well-proven, method of injecting a protein antigen directly. There are several candidate proteins on the surface of COVID-19 that could serve as antigens but these vaccines will be largely directed against the “spike” protein that is so visible in all pictures of the virus.

[Breaking down all of these further is beyond the scope of this article but they are summarized nicely in the Wall Street Journal (http://ereader.wsj.net/?publink=22b848ea3).]

An encouraging article in the New England Journal of Medicine showed that two vaccine candidates from BNT/Pfizer provided good immunogenicity and one of these (BNT1762b2)was selected to progress from phase 1 to phase 2-3. It had the better balance of reactogenicity and immunogenicity and was effective in the elderly as well as younger populations. [ClinicalTrials.gov number, NCT04368728 ]. There is a lag between acquiring the data in a study, analyzing it, writing it for publication, and then having it published. This means that by the time of publication, the trial had been underway for some time.

Moderna also appears close to opening its data and perhaps we will have information on this product before the end of the year. The phase 1 success of Pfizer/BioNTech augurs well for the Moderna product since the two employ quite similar technologies. Other companies and organizations are not far behind. There is talk of two Russian vaccines but they were approved after testing on very few people and their safety and efficacy are far from certain. The Chinese entry appears to be progressing and is in the process of being tested in a larger trial in China. All of this is quite fluid and the relative positions of these vaccines will change several times before this is decided. At the end, the FDA that will make the decision. It has held the line on quality and safety nicely in the face of political pressure and will make a good decision.

November 9, 2020

In a very encouraging update today, Pfizer/BioNTech announced an early analysis of results for their vaccine in a trial on 43,000 people. There were 90% fewer cases of symptomatic COVID-19 than in the group that received the placebo. This is based upon 94 cases of COVID-19 and the trial will continue until 164 cases are documented - a statistical requirement of the trial design. The company will not file for an emergency use authorization until half the patients in the study have been observed for two months following their second dose since most serious issues appear within that time period. This should be in the third week of November.

This apparent success offers additional support for the Moderna product which is designed and manufactured in a similar manner to the above.

November 16, 2020

Well, sooner than expected, Moderna announced today that the phase 3 trial of its mRNA vaccine on 30,000 people showed very good efficacy, The protective effect was 94% (probably not significantly different from the Pfizer/BioNTech result of 90%) and it also appeared to ameliorate the disease. The volunteer group included persons of various races and ethnic backgrounds as well as a wide age spread. This is very encouraging and the company plans to file for an Emergency Use Authorization within the next few weeks. Thus, we now have two very efficacious vaccine candidates that could be distributed within the next few months.

It is difficult to overestimate the significance of these results. I think never in the history of medicine has a vaccine been developed so quickly. Moreover, both have achieved a high efficacy not only in neutralizing antibody production but also in stimulating the cell-mediated immune response. (For a complete review of mRNA vaccines, please visit HHS Public Access author manuscript: Nat Rev Drug Discov. 2018 April ; 17(4): 261–279. doi:10.1038/nrd.2017.243).

November 23, 2020

Today, Oxford/Astra-Zeneca released data from its trial. Their efficacy was 90% using a regimen of a half-dose followed two weeks later by a full dose. They are using a modified adenovirus vector to deliver the nucleic acid which is then covered by the cells into the spike protein antigen that stimulaters the immune system. Thus far, thee is no information as to whether this will be released under the Emergency Use Authorization - or its equivalent - in the UK.

The important message is that it is becoming increasingly car that the “spike protein” is immunologically important and can be used to generate neutralizing antibodies. How one gets that antigenic stimulus into the host apparently is less important. This leads to the prediction that the Novavax spike protein antigen will prove to be equally efficacious when those trials are completed.

We now have good reason to hope for a decline in COVID-19 infections in the relatively near future. This does not mean that personal protective measures should be lessened. They are critical in managing the pandemic. Without them, the current increase in cases will be even higher. Continue to wear your mask and follow social distancing guidelines. The vaccine is not yet ready and probably will not be available for general use until late spring or early summer of 2021.

December 8, 2020

We now have three vaccines ready for distribution. It is almost impossible to overstate the astounding scientific feat this represents. Usually about ten years are required to develop and bring to market a vaccine. We have made three in about ten months. This was possible because Operation Warp Speed (perhaps a less pretentious title might have been better) removed the risk and allowed companies to develop and plan to manufacture before the vaccines were shown to be efficacious and safe. This was a proper function of government - support necessary projects that are too large for commercial or state governments to undertake by providing infrastructure or removing risk. This converted what is a sequential development path, that moves as fast as risk planning will allow, into a parallel path where the risk of failure has been removed. It truly was a Manhattan Project, but designed to save lives rather than take them. This is a medical and scientific triumph.

Now we must determine how best to distribute the vaccines and the order in which people will receive them. There will be endless speculation in the press but, in due course, a plan will be made public and we shall begin the halting of this pandemic. Great Britain began today by inoculating a 91-year old woman with the Pfizer/BioNTec vaccine. Let us hope that we will begin within a few weeks.

December 12, 2020

The FDA has approved the Pfizer/BioNTec vaccine and shipments will begin in a day or two.This speed is unprecedented. A usually ten-year process has been compressed into as many months.Distribution plans are in order and immunization of our high-risk population will begin within a week. Wear your mask. Don’t get careless and infected now.

December 18, 2020

Immunization is progressing smoothly with the most exposed health care providers receiving the vaccine now. Our concern also is for the elderly, in institutions and homes. There are 50 million people over the age of 65 in this country, and at the rate of manufacturing and delivery we now see in operation, we should be able to immunize all of them within about two months. Wear your mask. Don’t get careless and infected now.