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Covid 19 Vaccine. Where are we in the process? How will they work? What’s taking so long?

As the US passes 60,000 Covid 19 deaths and we begin to selectively reopen parts of the country, the race for Covid 19 vaccine is at full speed.  However, questions regarding how vaccines work, how they are made, how well they work and the approval proess are generally not known. Knowing this information will help set expectations for development speed and possible effectiveness.

Recent History.  In the last 10 years, several epidemics have caused rapid research and development of vaccines for SARS (Severe Acute Respiratory Syndrome), H1N1 influenza (Swine Flu), Ebola, Zika, and now SARS-CoV-2 (Covid 19).  In each case a vaccine was ultimately developed.  However, the SARS and Zika epidemics ended on their own before vaccine development was completed and the Ebola vaccine was made available around the time the Ebola epidemic was winding down on its own.

A separate discussion will be provided in another blog regarding the vaccines for seasonal flu.  For now, know that the seasonal flu, with a vaccine, comes back every year and causes 25,000-60,000 deaths each season.  Due to changes in the flu and the corresponding vaccine, the effectiveness of the flu vaccine has been as low as 15% for season and averages around 40% effective overall. https://www.cdc.gov/flu/vaccines-work/vaccineeffect.htm

History.  A vaccine is something that is introduced into the body that causes the body’s immune system to fight off infection by producing specific antibodies.   The first ‘modern’ vaccine was developed by a British physician, Dr. Edward Jenner in 1796.  He discovered that if he infected people with the related but much less deadly cow pox virus, these patients would develop an immunity to the very deadly small pox.  It is a long and difficult process to make a vaccine.  At the start of the 20th century, yellow fever and polio killed and infected millions.  However, diseases such as these diseases, small pox and measles are virtually eliminated from the developed world (where the vaccines are available).

What are vaccines and how do they work?  The human body has amazing ability to generate specific ways to kill harmful bacteria and viruses.  These harmful bacteria and viruses are often termed as pathogens.    Specifically, the body can make special proteins called antibodies which are made specifically to fight off a specific pathogen.  That is, the body makes a different antibody to fight off each kind of pathogen.

Antigens are characteristic molecular structures on the surface of pathogens.  It is the antigen on the virus that attacks and infects healthy cells causing the disease.  Fortunately, we have a type of white blood cell, called a B Cell Lymphocyte that can not only recognize antigens but also produces a specific antibody that binds to the specific molecular structure of the antigen.  Once the antigen is bound by an antibody, the antigen can no longer infect another cell.  Another feature of this system is that once antibodies are produced, the body will recognize these antigens if they appear again and immediately makes more antibodies to fight off the infection.  This is how we get immunity.  This simplified process description is depicted in the figure below.  A part of the virus (pathogen) is seen at the bottom of the photo.  On the surface of the pathogen are the antigens.  A cell is shown carrying antibodies (the purple Y shaped structures).  You can see that the one end of the antibody matches the shape of an antigen and binds to it.  This inactivates that antigen.  The B cell is then seen bursting releasing antibodies that can seek out and bind to other antigens.

There are three general approaches to make vaccines:

Weakened Virus.  In this method, viruses are weakened so they reproduce very poorly inside the body and will not cause illness.  However, they reproduce enough to produce antibodies.   The vaccines for measles, mumps, German measles (rubella), rotavirusoral polio (not used in the U.S.), chickenpox (varicella), and influenza (intranasal version) vaccines are made this way.   Vaccines made in this way cannot be used on people that already have weakened immune systems like cancer and HIV patients.

Inactivate (dead) Virus In this method, the viruses are killed (usually chemically) and introduced into a healthy patient.  The dead virus can not cause infection but the antigens are still on the surface and antibodies are made. The inactivated polio, hepatitis A, influenza (shot), and rabies are vaccines made from inactive viruses.  Vaccines produced in this manner can be given to those who are immunocompromised.  The limitation of this approach is that it requires the handling of large amounts of live virus and typically requires several doses to achieve immunity.

Use Part of the Virus. In this method, just one part of the virus containing the antigen is removed and used as a vaccine. These ‘parts’ can be DNA, RNA, recombinant DNA and protein units, to name a few.  The hepatitis B, one shingles vaccine (Shingrix®) and the human papillomavirus (HPV) vaccines are made this way.  This strategy can be used when an immune response to one (known) part of the virus is responsible for production of the antibody.  These vaccines can be given to people with weakened immunity and appear to induce long-lived immunity after two doses.  Most of the candidates in Phase I testing use this strategy (although in very different ways).

AN IMPORTANT CAVEAT.  This is a very, very simplified discussion of vaccines.  The actual mechanisms of action, chemistry, biochemistry and molecular biology are quite complex and well beyond the scope of this blog.  If you are interested, there are many references to the details on line.

Development of a Covid 19 Vaccine

On April 8, there were 115 Covid 19 possible vaccine candidates know/discussed.  However, only 78 of these are known to have become actual development projects.  It is unclear how many of these projects are still on going. Only 7 candidates have entered the first phase of human testing somewhere in the world. https://www.nature.com/articles/d41573-020-00073-5

There are several barriers to development of this vaccine.

It is not clear exactly how to prepare the vaccine.  Optimizing the antigen is difficult as it is not yet clear how much (or what part) of the full antigen protein is needed to illicit the appropriate antibody production.  Of the 7 vaccines in Phase I trials, no two use the same antigen preparation method.

There is always concern about causing side effects.  Preclinical trials during the SARS vaccine development raised concerns over exacerbating lung diseases.  As Covid 19 kills through a respiratory mechanism, this is an important concern.

It is not known how much of the vaccine (assuming you have the right one) is needed and if you need to use more than one dose to achieve immunity.

If you achieve immunity, it is not known how long the immunity will last.

Typically, vaccine development is a lengthy (10 year) expensive process.  As the manufacturing method is dependent on the actual way the antigen is prepared, manufacturers generally wait until they are fairly certain they have a successful vaccine before they invest the costly development and construction of manufacturing facilities and distribution plans.  There have been reports that some companies are taking a large risk by starting to develop manufacturing before they are even out of phase I trials in order to get the vaccine out as fast as possible.  It is quite a financial risk to do this as they may construct a facility that does suit their actual final product.

There are 3 Phases required for Vaccine Approval.

Phase 1.  A human trial with a small group (typically less that 100) of HEALTHY patients.  This is to insure that there are no ill effects of the vaccine and to see if any patients develop Covid 19 infections.   This phase usually takes a few months.

Phase 2.  This will involve a larger group of patients followed for a longer period of time.  The results from Phase I will help determine the number of patients and the length of the study.  Typically, this Phase involves hundreds of patients and can take 1-2 years.  However, due to the urgent need for the vaccine, shorter evaluations may be possible with the right study design and accepting higher risks.

Phase 3.  In this Phase thousands of patients will be vaccinated and the patients should be representative of the total population in terms of age, gender, ethnicity etc.  This will provide information on the effectiveness of the vaccine.  Again, the results of Phase 2 will dictate the exact number of patients and study time needed.

FDA Review.  At the end of Phase 3, the FDA will evaluate the results and provide approval, assuming safety and efficacy and patient protocols are demonstrated..

Phase 4.  The vaccine producer is generally required to continue clinical trials to look for additional side effects and study the longer term effects of the vaccine.

The global vaccine R&D effort is unprecedented in terms of scale, speed and diversity of candidates. Given the worldwide urgency, the most optimistic estimates are that vaccines could be available under ‘emergency use’ in the first half of 2021. This would represent an incredible change from the traditional vaccine development pathway time of over 10 years.  Introduction at this speed will require new development requirements, testing criteria and regulatory flexibility.   There is not substitute for letting nature act on its own time scale.  As the saying goes, ‘you can’t get 9 women and have a baby in a month’.

We should not forget that we do not want to sacrifice safety and efficacy for speed.

It is amazing that such a complex problem can have so many possible solutions being pursued simultaneously.  We truly live in amazing time in history.

Next: how well should we expect the vaccine to work?  The current antibody testing of larger number of patients has indicated that actual fatality rate is well under 1% and may be in the range of the seasonal flu.  This is very good news as the seasonal flu numbers include the use of a flu vaccine.  For Covid 19 to the same fatality rate without a vaccine provides some reason for optimism that with a covid 19 vaccine, it will be less deadly than the seasonal flu.New York: Nearly 3 million infections – not 276,000