THE Vaccine…and why don’t we have one yet.

Ever utter “A pox upon your house” to someone you really did not like? OK, probably not but most have at least heard of the phrase. “A pox upon your house” is a line from Romeo and Juliet. The word pox comes from the old English pocks which are pustules of disease being either syphilis or smallpox. To wish smallpox on someone was in Shakespeare’s time a curse for a painful death. Smallpox was a viral disease that was highly contagious and deadly. In the late 1700’s smallpox killed as much as 10% of the British population and over the last 100 years has been responsible for over 500 million deaths.

Today, the WHO has declared that the disease of smallpox has been eradicated. This successfully began when William Jenner popularized the use of cowpox to vaccinate people against smallpox. Smallpox was caused by the virus Variola major and minor. The death rate for those who contracted the disease was 30% and survivors were left with scarring and occasional blindness. The initial symptoms were a fever and vomiting.

20th Century Problems

Fast forward to the Spanish flu pandemic of 1918 when the influenza virus H1N1 infected an estimated 500 million people over a period from January 1918 through December 1920. Estimates put the death toll between 17 million and 100 million, or on average about 10%. The disease was spread by sneezing or coughing. One theory has the disease starting during WWI in France, and due to the close quartering, it spread rapidly. There was a second wave, more deadly than the first due to the circumstances of war.

In a naturally occurring pandemic, people with the more deadly form of the virus get sicker and stay home, while those with a mild form go about their business spreading the milder form. But during the war, those with the milder form remained in the trenches, and the sicker who could not fight, were transferred out to hospitals and thus spread the more virulent strains.

Curiously, a number of people died from aspirin poisoning after the Surgeon General and the Journal of the American Medical Association suggested that high doses of aspirin were curative. Bayer’s patent on aspirin ended at this time leaving room for other pharmaceutical companies to rush production and make large amounts readily available.

The pandemic rapidly decreased after the second wave. One theory as to why this happened is that the virulent strains kills early and thus is eradicated from the population while the milder strains remain. As time goes by the remaining virus is less virulent.

Pandemic circa 2009

Fast forward to the 2009 swine flu pandemic. In 1933, scientists discovered that viruses caused influenza and by 1939, Jonas Salk and Thomas Francis had developed a vaccine against the influenza virus. So how did H1N1 cause a pandemic in 2009 if there was already a flu vaccine? Because the virus mutated and the vaccines in use were ineffective against the new strain. The CDC reported that from October 1, 2019 to February 1, 2020, between 13,000 and 30,000 people in the US died from H1N1 influenza. There is a vaccine for H1N1 and it has been around since 2009.

The point: a vaccine is desperately needed against COVID-19 but having a vaccine will not make COVID – 19 go away. Yet, experience with H1N1 demonstrates that life can go on without drastic changes in daily lives and without economic disaster.

So why isn’t there a vaccine yet?

Vaccines work through the body’s own defense system called the immune system. The body has a system of white blood cells that are designed to kill anything that the system does not recognize. Examples are cancer cells, dead cells, bacteria, and viruses. When the system is first exposed to a virus, it releases proteins called antibodies (IgM) which label the virus as foreign so that another set of white blood cells can kill the virus. Measuring the IgM antibody is the basis for COVID-19 testing of individuals suspected of having active disease. Once the system is exposed to virus and has mounted an immune response, it has a system of cells that will remember that virus. If the virus comes back, the immune system can mount an attack using proteins called IgG antibodies. This response is much quicker and thus the virus cannot establish itself, and the infection is averted.

IgG testing can be used to determine who has become immune to the particular strain of COVID-19 that the individual had. Having immunity to a particular form (strain) of the COVID-19 does not protect the person if the virus mutates to a different form, if the initial immunity did not develop, or if the person is old and their immune system is weak. Vaccines are designed to stimulate an immune reaction in a person without them actually getting the disease. Once the immune system has mounted a defense, the memory cells can reduce or prevent the flu.

The development of a vaccine the COVID-19 would alter the course of the disease by creating a protective immunity in the individual who was vaccinated but also reduce the number of non-immune people from getting the virus. COVID-19 was such a new mutation (change) in the coronavirus that there are no readily available vaccines. The ones that are in existence simply do not recognize COVID-19 as a deadly virus.

The business of vaccine development

As of early April, there were at least 86 different vaccines being developed around the world. Some vaccines are already in Phase I trials. A Phase I trial is designed to assess the safety, side effects, and the immune response the vaccine causes. A few of the vaccines have been approved for Phase II trials which are larger trials that evaluate the efficacy of the vaccine. Phase III trials evaluate the efficacy and safety of the vaccine for a much larger group of volunteers. If the vaccine meets the standards set by the trial, then manufacturers can apply for approval to manufacture and release the vaccine for general use.

Getting the vaccine to general use carries significant prestige for the scientist, the manufacturer and perhaps the country. If China is first, one could argue for the Chinese form of government. Furthermore, there are approximately 5 billion doses of vaccine made each year worldwide, with 1.5 billion for seasonal flu. But if countries are not able to increase production and one country has enough production only for their own population, the distribution could get very nasty.

The mechanics of a vaccine

The substance that incites the immune system to recognize a virus or bacteria is called an antigen. The virus goes into the type of cell it is deigned to infect, such as those of the respiratory system, and makes new virus. Some of the virus is moved to the surface of the cell it has infected which alerts the immune system that the virus has infected the person. There are other ways to present the virus to the immune system such as immune cells ingesting parts of the virus directly. Once the immune cells mount a defense, they release proteins, antibodies, which attach to the antigen wherever they find it. Bonding the antibodies to the virus can prevent the virus from binding to cells of the respiratory system and signal other immune cells to dispose of the virus.

The way to present the antigen to the immune system can be done in a number ways. One way is to use a defective COVID-19 virus that would not cause disease. This method has been used for vaccines for measles, mumps and rubella. Another way is to use an inactivated COVID-19 virus. This method is used for polio and seasonal flu vaccines. The advances in molecular biology has permitted the synthesis of the antigens without the virus. Finally the gene for the antigen can be put into another safe virus and a person can be infected with this innocuous virus. This method was used to produce the Ebola vaccine. One vaccine of this type is being entered into Phase II trials. In spite of all of these approaches, none have been licensed yet.

Other issues

The type of vaccine is not the only issue. The dose is important. Some vaccines need to be given more than once. Some vaccines need to be bound by other substances, which are called adjuvants, that enhance the ability of the vaccine to trigger an immune reaction. Safety is an important concern. Some antibodies can actually make the disease worse, an occurrence which was recently demonstrated by the vaccine developed to fight Dengue fever. Finally the vaccine needs to be evaluated for efficacy: does it actually work?

Interestingly, there is not much profit to be made from vaccines. Most vaccine production is confined to four companies. Pandemics are devastating but limited in time so that once the pandemic is done, there is no use for the vaccine and the companies have a vaccine with little or no use. For example, after the H1N1 pandemic of 2009 subsided,governments cancelled contracts for the vaccine and the manufacturers were left with substantial developmental costs and no way to recoup their loss. Also if companies ramp up production for COVID-19 vaccines, they will necessarily reduce the production of other vaccines which could escalate the incidence of the diseases those vaccines were designed to fight. Some members of the pharmaceutical industry contend that there is no excess capacity and in fact there is a shortage already of some vaccines…for example measles.

If a second wave of COVID-19 coincides with seasonal flu, this would seriously stress the capacity to make sufficient vaccine for both diseases. To assure sufficient production, governments could assure industry that their expenses will be covered. Some companies have agreed to increase production if needed and produce the vaccines on a not for profit basis.

However, it is possible, even probable, that there will be disparities in availability for the vaccine. This could create significant ethical dilemmas as to who gets the vaccine and who does not. This is already in the works as the G20 has asked the WHO to coordinate these efforts.

In this century and even in the last, vaccines have become a given for most of us. So, when a new player such as COVID-19 comes on the scene, it’s hard to imagine why a novel vaccine can’t simply be put in place. If only it were that easy, the poxes of Shakespearean literature would cease to exist.‌

Dr. John Rinehart

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