December Newsletter
In This Issue
The Vaccines are Here!
Vaccine Q&A
A Better Model of Medical Care
Old-fashioned medicine with 21st Century convenience and technology
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Welcome to the December newsletter. The goal of this newsletter is to provide information and analysis of timely topics from recent articles published in the  medical literature. I hope you find this information useful and helpful in your health journey.   
We now have two vaccines in use here in the United States and a few more on the near horizon. This is obviously the biggest health care story of the year. We have started vaccinating health care workers and long-term care residents. Development of these vaccines is unprecedented both in speed of development and technology. The virus was first sequenced in January and in 11 months we developed an effective vaccine. Our technological advancements over the past decade all came to fruition. Never in history have we developed a vaccine so quickly. This month I am going to give a rundown of the vaccines currently available (Pfizer and Moderna) as well as the vaccines on the near horizon (AztraZeneca, Johnson & Johnson, and Novavax). What is amazing is that these vaccines are all different and we have 4 different types of vaccines in the group!

We all have questions about the vaccines. Are they safe? How could we develop vaccines so quickly? What if I already had COVID-19, should I get vaccinated? Who will get it and when? When will it be available in Wisconsin for me? Read on to hopefully get the answers you need. 

As we bid 2020 farewell (good riddance, actually), we would like to wish you and your families all the best in 2021!

Information regarding COVID-19 is constantly changing. Cases and hospitalizations here in Wisconsin are thankfully trending downwards and we are now less than 60% of our peak. If you are feeling sick or concerned about symptoms, please call me first. We can discuss your symptoms and decide the best course of action for you, including testing and therapeutics. I have saliva based COVID-19 PCR tests available in my office with 24+ hour turnaround. Serum antibody tests can be performed as well with 24-hour turnaround. Please continue to wash your hands frequently, use a mask indoors when around others, avoid touching your face, and avoid going out if you are sick.   
The Vaccines are Here!
Rundown of COVID-19 Vaccines
Development of the Covid-19 vaccines has been unprecedented in human history. The genetic sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are being used for vaccine discovery and manufacturing. As of December 27, 2020, The New York Times Coronavirus Vaccine Tracker listed 64 vaccines in human trials, and at least 85 preclinical vaccines were under investigation in animals. Some methods have been used in the development of previous vaccines, whereas others are newly developed. For example, mRNA vaccines (like the Pfizer and Moderna vaccines currently available) for influenza, rabies, and Zika virus have been previously tested in animals.

On December 28, 2020, the National Institutes of Health announced the fifth phase 3 trial for COVID-19 vaccines (NVX-CoV2373) in the United States has begun enrolling adult volunteers. 

According to recommendations of the Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices, the first 2 groups to get the vaccines will be healthcare workers (1a) and residents of long-term care facilities (1b). Phase 1c would include adults with high-risk medical conditions and those aged 65 years or older.

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variables that increase complexity of distribution include storage requirements (frozen vs refrigerated) and whether more than a single injection is required for optimal immunity. Several technological methods described below (DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development and the type of technological method used to develop the vaccine determines the vaccine attributes (number of doses, speed of development, scalability).

Information on the five vaccines in late-stage development which are currently approved or nearing approval is below.

BNT-162b2 (Pfizer - currently in use) is a nucleoside-modified messenger RNA (mRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. On December 11, 2020, the FDA granted EUA for the BNT-162b2 SARS-CoV-2 vaccine in patients 16 years and older on December 11, 2020, after its VRBPAC voted to recommend (17 yes, 4 no, 1 abstention) the EUA on December 10.

  • Genetic-code vaccine
  • Storage and shipping requirements: Frozen; ultra-cold storage of -70ºC
  • Requires reconstitution
  • Once thawed, stable while refrigerated for up to 5 days
  • Room temperature stability: 2 hours
  • Dose: 2 intramuscular injections in deltoid muscle 21 days apart
  • 95% effective, well-tolerated across all populations
  • Not evaluated for asymptomatic infection/carriage
The ongoing multinational phase 3 trial included 43,548 participants 16 years and older who were randomly assigned to receive vaccine or placebo by injection; 43,448 participants received vaccine or placebo (vaccine group, 21,720; placebo group, 21,728). Approximately 42% of global participants and 30% of US participants were of racially and ethnically diverse backgrounds, and 41% of global and 45% of US participants were 56-85 years of age.
Vaccine efficacy was 95%, and no serious safety concerns were observed. The only grade 3 adverse event with a frequency of greater than 2% was fatigue at 3.8%; headache occurred in 2% of participants. Short-term mild-to-moderate pain at the injection site was the most commonly reported reaction, and severe pain occurred in less than 1% of participants across all age groups.

mRNA-1273 (Moderna - currently in use) is an mRNA vaccine which encodes the S-2P antigen. On December 18, 2020, the US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for the mRNA-1273 SARS-CoV-2 vaccine in individuals 18 years and older, after its Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to recommend (20 yes, 0 no, 1 abstention) the EUA on December 17.

  • Genetic-code vaccine
  • Dose: 2 injections 28 days apart
  • No dilution required
  • Shipping and long-term storage: Frozen (-20°C) for 6 months
  • After thawing: Standard refrigerator temperatures (2-8°C) for 30 days
  • Room temperature: Up to 12 hours
  • 94.1% effective, well-tolerated
The US phase 3 trial (COVE) launched on July 27, 2020. The trial was conducted in cooperation with the National Institute of Allergy and Infectious Diseases and included more than 30,000 participants who received 2 100-µg doses or matched placebo on days 1 and 29. The primary efficacy analysis was released November 30, 2020. The COVE study included Americans 65 years and older, younger individuals with high-risk chronic diseases, individuals who identify as Hispanic or Latinx, and individuals who identify as Black or African American.

AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) is a replication-deficient chimpanzee adenoviral vector vaccine containing the surface glycoprotein antigen (spike protein) gene. This vaccine primes the immune system by eliciting antibodies to attack the SARS-CoV-2 virus if it later infects the body.

  • Viral vector vaccine
  • Phase 3 trial was temporarily put on hold globally on September 6, 2020 after a study participant in the United Kingdom was diagnosed with transverse myelitis. After FDA review in the United States, phase 3 trials resumed here on October 23, 2020. 
  • Storage: Refrigeration 
  • Dose: 2 injections 28-days apart (half dose then full dose most effective)
  • Efficacy 90%
  • United Kingdom approval expected soon. Phase 3 trial in US is ongoing.
  • Owing to the testing of a different coronavirus vaccine last year, development for AZD-1222 was faster than that of other viral vector vaccines.
Ad26.COV2.S (Johnson & Johnson)

  • Viral vector vaccine
  • Storage: Refrigeration
  • Dose: 1 injection (antibodies observed after single injection)
  • 99% positive for antibodies at day 29 and strong T-cell and T helper cell responses noted.
  • Application pending in Canada and Europe
NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate an antigen derived from the coronavirus spike protein.
  • Subunit vaccine
  • Dose: 2 injections, 21 days apart
  • Results of preclinical studies showed that it binds efficiently with human receptors targeted by the virus.
  • Phase 1 data in healthy adults showed that the adjuvanted vaccine induced neutralization titers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19.
  • Phase 3 trial in the United Kingdom has completed enrollment of 15,000 participants, including more than 25% who were older than 65 years.
  • Researchers conducting the US and Mexico phase 3 trial, which started in December 2020, plan to enroll up to 30,000 participants.
In addition to these 5 vaccines which are in use or in stage 3 trials, there are 19 other vaccines in later phases of development using various technologies. These include a DNA based 2-dose vaccine which will be stable at room temperature for over 1 year, additional mRNA vaccines, a vaccine using Ebola vaccine technology based on modified measles virus, antigen vaccines, self-assembling nanoparticles, T-cell activating platform, inactivated whole viron, and recombinant adenovirus (among others). Additionally, there are a number of noninjectable vaccines in development including intranasal, inhaled, oral, and transdermal.

Moving forward, I expect that there will be multiple vaccines available over the next few months. I would expect that if this is an annual or somewhat frequent immunization (3-5 years) that one of the single dose, easily stored vaccines will be the most commonly used. 
Vaccine Q&A
As we move forward with vaccination, many of us have questions. 

Will this vaccine give me COVID-19? 
  • No, it will not. None of the vaccines in use or undergoing development have intact virus in them. The mRNA vaccines don't use any part of the coronavirus itself. They use manufactured mRNA molecules that carry instructions for building the spike protein of the virus. The vaccine causes the cells to take up the mRNA and use it to build the spike protein and display it on their cell surfaces which triggers the immune system response. The mRNA does not enter the cell nucleus or interact with cellular DNA in any way. The mRNA degrades quickly so it is delivered encased in a protective lipid membrane.
Are these vaccines being made too quickly? 
  • Researchers have been working on mRNA vaccines since the 1990's. They have been tested in animals for many viral diseases. These vaccines are easily manufactured from common materials. While making a vaccine available usually takes years, we have never had a situation where the entire focus of multiple companies has been on a single goal and there has been near unlimited money to pursue vaccine development. Additionally, advances in technology over the past decade have now allowed us to sequence the viral proteins, RNA, and develop the vehicles to deliver the mRNA into the cells successfully. We also had a restructuring of the normal vaccine development process. The same phases of development; animal testing, a small initial human phase, a second for safety testing, a third large phase for efficacy were all conducted as for any vaccine. But in this case, some phases were completed in parallel, rather than sequentially. This approach has proved so successful that there is already talk about making it the model for developing future vaccines. Two other factors contributed to the speed. First, companies ramped up production even before anyone knew if the vaccines would work. The second factor has been the large number of cases, making exposures more likely and thus accelerating the results of the efficacy trials. There have been so many cases of COVID being transmitted everywhere in the United States that it did not take long to hit the threshold of events to reach the goals of phase 3 trials. The "Operation Warp Speed" part of the development refers to the manufacturing and distribution of the vaccine, not speeding through the development or safely testing of the vaccines.
How do we know it's safe? This vaccine has never been used in humans. 
  • The phase 3 trials of the Pfizer and Moderna vaccines included over 73,000 people and have 9 months of follow up. Monitoring is continuing. There were a very small number of allergic reactions (0.63% in the vaccine group and 0.51% in the placebo group). At this point over a million people have been vaccinated and there are no large reports of problems outside of a few side effects and an allergic reaction.
What are the likely side effects? 
  • The most common side effect is pain at the injection site and an achy, flu-like feeling. These common side effects are considered a "good" sign as they indicate a robust immune response. This response is similar to what some people have experience with the newer Shingrix (shingles) vaccine.
What about children? 
  • At the present time neither vaccine is approved for children under age 16 (Pfizer) and age 18 (Moderna). There are trials ongoing for both vaccines currently and approval for children over age 12 is likely forthcoming soon.
I already had COVID-19. Do I still need to get the vaccine? 
  • There are too many unknowns to know if having COVID-19 gives long lasting antibodies after infection. We know that a vaccine tends to produce antibody titers at the higher end of the spectrum which suggests better immunity from vaccination that natural infection, especially a mild infection.
What is going on with vaccine distribution in Wisconsin? 
  • The week of 12/21/20 Wisconsin received 35,100 doses of the Pfizer vaccine. Over the next 2 weeks we are expected to receive 100,000 doses of the Moderna vaccine. At this time health care workers have started receiving the vaccine through hospitals and this week Skilled Nursing Facilities will begin to receive vaccines administered through CVS and Walgreens. Moving forward, the next group to be eligible for vaccines will be essential workers and then people over age 65 and immunocompromised people. It appears that much of the distribution of vaccine in the community will occur through CVS and Walgreens. I have my application in to be a site for vaccine administration, but I suspect it will be a while before small offices have vaccine available so my recommendation for most of you would be to get the vaccine wherever you can when it is available for your age and condition. I will let all members know when I have vaccine available.

Thank you for taking the time to read through this newsletter. I hope you have found this information useful as we work together to optimize your health. Feel free to pass this on to anyone you think would benefit from this information. 

You can find previous newsletters archived on my website here


As always, if you have questions about anything in this newsletter or have topics you would like me to address, please feel free to contact me by email, phone, or just stop by! 

To Your Good Health,
Mark Niedfeldt, M.D.