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Medical Bits – Vol. 3.2: Your Health and Medical News

Pandemic Update – Vaccination Progress

Despite our curiosity and yearning to answer many other questions, the Coronavirus Pandemic remains at the center of our lives and therefore, I decided to address what I hope will be the last “Update of Updates” on the subject!

There are so many “certainties” provided by modernity and science, that it is easy to forget that many ailments and consequent human suffering have been vanquished thanks to the application of the scientific method and the development of vaccines.

Since 1796, when the concept of vaccination was born, and more than 100 years before viruses were identified as causative agents of disease, humans have learned to use their ingenuity to prevent them. Here, you will find a brief history of vaccinology from Jenner’s cowpox to mRNA Covid vaccines. It is sobering to remember that Smallpox killed more than 300 million people in the 20^th century alone and the Influenza pandemic of 1918 caused over 50 million deaths.

We continue to emphasize that we should be joyous and grateful to have safe and effective vaccines that were developed promptly to counter this global challenge.

At this time, there are ten vaccines against COVID-19 approved in different nations. There are several more in the pipeline. In the US, three vaccines have received Emergency Use Authorization (EUA). Two mRNA vaccines were deployed in December 2020. The Pfizer – BioNTech and the Moderna – NIH-NIAID and received preliminary approval and EUA. These vaccines had an impressive 95% efficacy and safety, as reported in their phase IIB-III clinical trials. Both require two injections, but early protection was noted as early as 12 days after the first injection. In the period between injections, the efficacy was almost 75% and the likelihood of severe disease declined even further. On February 27^th, the Johnson & Johnson modified adenovirus vaccine received EUA and it joined our armamentarium.

Many of you have questioned the efficacy of this “newcomer”, noting that the reported efficacy was “only” 66%. The main difference is that the new “jab” was tested in nations such as South Africa, where almost all of the circulating viral strains were the new B.1.351 and other similar variants. One dose of the modified adenovirus vaccine was 66% effective in preventing mild to moderate COVID-19, but 100% effective in preventing COVID-19 related hospitalizations and deaths. Therefore, we should get those arms ready and get the JAB that comes our way! No reason to waste time or be “choosy”. Vaccine efficacy will change according to the outcome or end-point we are considering, which is well explained here.

Two weeks ago, results of the large phase III clinical on the vaccine developed by the University of Oxford – Astra-Zeneca were announced. The two-shot vaccine, tested in over 32,000 volunteers in the US, Chile and Peru, showed a 79% efficacy preventing even mild disease and was 100% effective against severe disease or hospitalization. As you may be aware, full results have not been published and data may not be complete. Yet, as you can review in the NEJM this past week, a novel HIV-vaccine candidate yielded negative results. Despite over 30 years of active world-wide research, HIV (RNA-retrovirus) has been able to avoid a global, one-step solution.

As discussed in our last “Bits”, Israel has been the nation with the highest share of their population vaccinated. By February 1^st, the number of hospitalizations among those over-60’s dropped precipitously! Three weeks before, 70% of them had already been vaccinated.

We now have some results published from hospital systems in the US and the results are equally encouraging.

Early Results of SARS-CoV-2 Vaccination – University of Texas, Southwestern Med Center.

COVID-19 Variants and Mutants

There are multiple variants of the SARS-CoV2 – Coronavirus across the world, classified by the Centers for Disease Control (CDC) as Variants of interest, of concern and of high consequence. The three variants of high consequence and concern have become dominant: The B.1.1.7 (first found in the UK in December 2020); the B.1.351 (first described in South Africa in December 2020) and the P.1 variant (first reported in Brazil in January 2021). They all increase the binding affinity (bonding ease and strength) to the ACE-2 receptors in the respiratory epithelial cells which leads to increased infectivity. But no such evidence for the lethality of infections.

Two new variants, B.1427 and B.1.429 have been described in California and appear to be 20% more transmissible than older variants.

But, as indicated in the past, despite the drum-beat of worrisome news about novel strains of the virus, we should remain optimistic! The vaccines all appear to make serious disease rare! While disease may still occur, particularly with the P.1 and B.1.351 variants, disease leading to hospitalizations in vaccinated individuals appears to be uncommon. And data from the clinical trials indicates that infectivity in those vaccinated is decreased by at least 70%. Information from Israel suggests that in the few individuals that develop infection after vaccination, the viral load is much lower, making them less infectious.

When will we reach “heard immunity”? All adults should be eligible for vaccination by May 2021, but not all want to get The Jab, which complicates matters, as discussed in prior “Bits”. In the meantime, remain vigilant! Despite significant progress and declining mortality, we are now seeing an uptick in infections which may result in a reversal of those gains.

The SARS-CoV-2 virus relies on its Spike protein to attach to the epithelial cell of the respiratory system to infect the individual and become internalized into those cells to hi-jack the metabolic machinery to replicate. Vaccine development has focused on this protein and all of them inoculate conformational variants of the Spike protein via different means (mRNA particles encoding for them – proteins – attenuated viruses that expose the same antigen protein and inactivated viruses).

We have discussed the different types of vaccines in the past. The P.1 and B.1.351 mutants, share a mutation that leads to a conformational change in the Spike protein and thus, appear to make the vaccines less effective, requiring higher neutralizing antibodies titers (NAb). Fortunately, the immunogenic response and titers of antibodies induced by vaccination appears effective, but less so with these variants.

The good news is that science and technology are keeping up with these mutants. Vaccine makers are already tweaking the vaccine and a few are developing “multivalent” vaccines for full protection against different strains. It is also possible that we may need a booster vaccine to cover new variants in the future. In fact, Britain’s National Health Service, which is planning to vaccinate all “willing” adults by the end of the summer, is planning to deploy a “booster” shot to cover new variants by the fall. Here you will find an excellent review of New Variants and Mutations.

A summary from the NEJM follows in this table.

The only reason to wait for the recently approved Johnson and Johnson vaccine or the Novavax vaccine (should be approved soon) is a prior history of polyethylene glycol intolerance. These vaccines can be stored in regular refrigerators and the Adenovirus-based Johnson & Johnson requires only one shot which should help with the logistics of distribution in other nations with less infrastructure.

We should pause and remember that not only the vaccine was developed in 10 months, but also it is amazing that new technology developed over the course of the past two decades came to our rescue and allowed biotechnology companies to use genetic engineering to manufacture antigen and deliver this important achievement!

As indicated on prior “Bits”, vaccines against viruses historically used “attenuated” or debilitated strains of the virus to coax the body to build defenses but not cause disease. The novel vaccine development has used genetic engineering, targeting the gene for the distinctive Spike protein that studs the virus’ membrane hoping it would provoke a brisk immunogenic response. Other joint ventures used the spike gene, inserting it into the genome of a harmless adenovirus which after infecting human cells it too, makes them produce spike proteins that trigger an immune reaction.

The frequently updated Coronavirus Vaccine Tracker from the NYT is an excellent resource. As mentioned, there are now 10 vaccines approved in different nations, 20 have reached the final stages of clinical trials and researchers continue to test 69 vaccines. Another excellent Covid-19 Research update from Nature.

Covid-19 Mortality Risk

You have all read about pre-existing conditions and other risk factors that increase the risk for potentially bad outcomes. These are the same risk factors that increase mortality from most other illnesses as well. Humans with hypertension, pulmonary disease, diabetes and obesity are known to have worse outcomes when confronted with serious disease.

We have discussed in the past the obesity “pandemic” that afflicts humanity. Not only the rising waist line increases the risk of diabetes, cardiovascular diseases, osteoarthritis and sleep apnea but also several cancers. We know that obesity leads to a chronic inflammatory state that decreases the cellular immunity mediated by T lymphocytes.

Obesity, Immunity and Cancer. N Engl J Med 2021; 384:1160-1162

These risk factors have now been refined by researchers from our University of Maryland and Johns Hopkins into a Covid-19 mortality calculator

This graphic from the CDC will remind you to lose weight!

Vaccine allocation

After an initially bumpy deployment, inoculations are proceeding well and ahead of anticipated goals, despite some ongoing frustrations. As we have discussed, physician offices have not been part of the distribution effort and therefore, at present do not have access to vaccines.

For specific immunization plans review your state: Maryland – for vaccine registration.

Montgomery county: https://www.montgomerycountymd.gov/covid19/vaccine/

CCACC

Dennis Ave. Health Center

Richard Montgomery High School

Quince Orchard High School

District of Columbia – for vaccine registration or call 855-363-0333.

Virginia – new comprehensive website.

Select CVS Pharmacies (according to local vaccination guidelines).

Select Walgreens Pharmacies (according to local vaccination guidelines).

Vaccine distribution nationwide is accelerating and is now up to 2.5-3 million doses daily! More than 100 million people have received one dose and more than 55 million are fully immunized.

National and International Vaccine Rollout information.

This NYT link has National and International Vaccine Rollout information.

As you may know, our federal government has ordered almost a Billion vaccine doses. There is a looming “Glut of Vaccine” which we will probably confront by May 2021. Clinical trials involving children and adolescents will likely not be completed till the Fall of 2021, further complicating things.

Allow me to repeat:

What can we do to prevent infection and disease?

Keep cool, eat a nutritious and diverse diet, stay active and be happy!

AND EXERCISE!!!

If you have 7 minutes daily, you can start to improve your fitness right now, and 11 more minutes will get you in shape!

Use a properly fitted mask while in public indoor places and forget to mask when outdoors (important to keep your sanity!) and remain vigilant!

Take a multivitamin daily and don’t forget your 1000-2000 IU of vitamin D3. Possibly Zinc 11mg supplements. Ivermectin, Hydroxychloroquine and Azithromycin have all been debunked.

Be ready to accept the JAB as soon as possible!

And let’s continue to make the best lemonade with the “lemons” nature has thrown our way!

Fear is not a rational response. This too shall pass! Do not anguish about rare problems unless you have won the lottery more than once.

Remember that the only certainty in life is… death… and the only fountain of youth proven by science, experience and millennia are exercise, laughter, humor and a good positive attitude!

Let’s try to concentrate on better times ahead and continue to enjoy every minute of this most interesting JOURNEY and cherish your family time!!!

Carlos E. Picone, MD

5215 Loughboro Rd NW, Suite 400

Washington, DC 20016

301-656-7374

cpicone@chevychasepulmonary.com

References:

https://www.nejm.org/coronavirus https://www.cdc.gov/coronavirus/2019-nCoV/index.html

https://www.who.int

https://clinicaltrials.gov/

https://www.nature.com/articles/d41586-020-00154-w]

https://science.sciencemag.org/content/early/2020/05/12/science.abc5312

https://www.nejm.org/doi/full/10.1056/NEJMp2005630?query=featured_coronavirus

https://www.youtube.com/watch?v=-Gn8oJY1VHY&feature=youtu.be

https://www.cfr.org/backgrounder/what-world-doing-create-covid-19-vaccine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805090/

https://www.nejm.org/doi/full/10.1056/NEJMcibr2009737?query=featured_coronavirus https://jamanetwork.com/journals/jama/fullarticle/2767840

https://www.nature.com/articles/d41586-020-00502-w

https://www.nap.edu/catalog/25914/discussion-draft-of-the-preliminary-framework-for-equitable-allocation-of- covid-19-vaccine

https://www.economist.com/briefing/2020/11/14/an-effective-covid-19-vaccine-is-a-turning-point-in-the- pandemic

https://www.economist.com/briefing/2021/02/13/vaccine-hesitancy-is-putting-progress-against-covid-19-at-risk https://www.nature.com/articles/d41586-020-00502-w

ANNEX:

Q & A

1. Are some vaccines better than others?

We do not know the answer to this question, as no comparative studies have been completed and they are not likely to be undertaken soon. It is very difficult to compare clinical trials, as all have different parameters, antigen dosing, interval between injections and population studied. We should be ready to accept any vaccine that comes our way!

2. Are the vaccines safe? Can they possibly aggravate pre- existing conditions? What is the duration of protection?

These are all important questions and the answers are ongoing. The clinical trials available for full review demonstrate that the vaccines triggered an excellent immunologic response across all age groups, were highly protective and caused minimal injection-site reactions and fatigue/malaise and occasional headaches (symptoms that are generally attributable to all vaccines and due to the immunogenic response triggered by the introduced antigens). The protection is anticipated to last at least 6-12 months and possibly longer as the cellular immunity is long-lasting and appears to be triggered as well. The incidence of anaphylactic reactions (mostly in those with polyethylene glycol intolerance) is below 5/million inoculations and develops within 20 minutes of administration.

3. Could the messenger RNA vaccines get integrated into my DNA and cause mutations or long-lasting ill-effects?

No. This is biologically impossible. The small messenger RNA is quickly broken down and does not interact with humans’ DNA. Both vaccines have a tiny segment of mRNA encased in lipids.

4. Are all Coronavirus tests the same?

No. One is the virus test, to learn if you are actively infected and the other is the antibody test to learn if you have been infected in the past and have immunity. The most accurate virus test is the Polymerase Chain Reaction – PCR which identifies the gene of the virus in nasopharyngeal secretions or saliva. It is more accurate but more expensive and labor intensive. Rapid tests identify specific viral antigen or coronavirus proteins implying active infection. They are less accurate but economical and faster.

5. Where can I be tested?

Locally, there are several sites (Sibley Hospital – 202-537-4190 but best to have an order from your doctor sent in advance; Kelly Goodman, NP offers testing through Capital Dx – 202-684-7167; AllCare Family Medicine 301-825-8880 in Glen Echo; ARCpoint labs in Spring Valley 202-880-3389 and MedStar Urgent Care in Chevy Chase 301-215-9440. You must call for an appointment in advance. There are now mail-options: CareCube and Pixel by LabCorp, will mail a test and you send back a sample with results within 12 to 34 hours and 36 hours respectively.

6. Asymptomatic individuals do not transmit COVID-19. Myth! Multiple studies indicate that nearly ½ of transmissions are from people not feeling ill and about a third of all infected patients remain asymptomatic.

7. Do antibodies last and could I get re-infected with COVID-19? The fact that after millions of cases worldwide only a few cases of re-infection have been reported is good Antibodies last several months and our cellular immunity takes over after antibody titers wane.

Antibody titers appear to remain elevated for 4-5 months after infection and then they start to decline. Gleaning information from the SARS-CoV1 epidemic of 2002, adequate titers of neutralizing antibodies remained elevated 2-3 years after acute infection.

8. COVID-19 is associated with increased risk of clotting and therefore we should take aspirin or blood thinners. Patients who develop severe COVID-19 disease and usually those requiring ICU support, may go on to develop small clots and disseminated intravascular coagulation. For those patients, anticoagulation treatment may be warranted and is decided by the ICU team at the time of care. Use of preventive blood thinners is unfounded!

9. Is the virus mutating to be able to be infectious through the skin? No! There is no evidence that this is possible. The virus utilizes special receptors located in the respiratory epithelium called ACE-2 (Angiotensin Converting Enzyme type II) to be internalized and infect epithelial cells. Furthermore, the probability of becoming infected from packages and surfaces is extremely Stop wasting time and disinfecting surfaces and packages. Not likely to get to your upper airway in an adequate infectious dose.

10. Is the virus mutating such that development of an effective vaccine is in peril? Of course, the virus is mutating, just like any other virus multiplying in the trillions and infecting millions of hosts. As discussed, some of the mutations may lead to increased infectivity but more “aggressive” behavior and potential to cause worse disease has not been seen. SARS-CoV2 is a stable, non- segmented RNA Yet, the infectivity of the virus appeared to have increased early on in the pandemic as a result of a specific mutation carrying the spike protein D614G substitution, augmenting the virus infectivity and becoming the dominant strain causing disease in Northern Italy and the most prevalent variant throughout the world for most of 2020. Now, new variants with heightened infectivity are at work such as B.1.1.7 which are displacing other less “efficient” strains. This continues as indicated above.

11. UV light / silver and copper-based agents destroy SARS-CoV2 and are effective preventive or treatment modes. Myth!

While prolonged UV light may inactivate the virus, using UV light has no immediate effects and is potentially harmful. Metal-based products have no known effect on the virus

12. Do masks help decrease the severity of illness and could they diminish Influenza transmission? Likely YES! There appears to be a relationship between the infectious dose and severity of The rate of asymptomatic infection was estimated at 40% by the CDC in mid-July, but they have been reported to be > 80% with universal masking. In a closed Argentinian cruise ship outbreak, where all passengers and staff were provided with masks, the rate of asymptomatic infection was 81% (compared to 20% in earlier ship outbreaks).

13. Should people who recovered from COVID-19 infection be vaccinated? YES! It is not certain how long the immunity will last, and although long term humoral and cellular immunities are anticipated, the recommendation is to be vaccinated 90 days after the acute infection.

14. Are people who cough or sneeze more infectious than others? Transmission appears to be driven by the viral load of index cases. A higher viral load also increases the risk of developing symptomatic disease shortens the incubation period in a “dose- dependent” manner, as reported by The Lancet.

ANNEX: COVID-19 Timeline

From Nature:

21 December, 2019, a few patients became ill with severe pneumonia in Wuhan, Hubei province of
31 December, 2019, a new virus is identified in samples from 4 patients with pneumonia of unknown cause. All patients had been present at the Huanan Seafood Market in Viral genome isolated and sequenced. Initially named 2019-NCoV (Novel Coronavirus 2019).
8 January, 2020 – Nature reports on the new virus, cause of mysterious “deadly pneumonia” in Wuhan,
21 January, 2020 – First US case confirmed in Washington 30 yo man returning from Wuhan, China.
23 January, 2020 – China closes Wuhan.
24 January, 2020 – Second US 60 yo woman returning to Chicago after visiting China.
28 January, 2020 – Human-to-human transmission confirmed in
3 February, 2020 – Study of live virus published.
6 February, 2020 – Retrospective autopsies completed in mid-April in Santa Clara, CA confirms that first deaths occurred in early Feb.
14 February, 2020 – Chinese authorities reveal number of infections in medical staff: 1,716 health workers had contracted the virus, 6 of whom died
17 February, 2020 – First case in Africa
25 February, 2020 – S. emergency funding for coronavirus response
26 February, 2020 – Brazil reports first case in South America
28 February, 2020 – Coronavirus spreads to sub-Saharan Africa
4 March, 2020 – Multiple drugs under investigation for coronavirus
5 March, 2020 – China study suggests children are as likely to be infected as adults, but most do not become ill.
11 March, 2020 – Transgenic animals for CV research in high demand
11 March, 2020 – Coronavirus becomes a pandemic, says WHO.
13 March, 2020 – US President declares “national emergency”. It is no longer a “Chinese virus that will blow over by the spring”.
17 March, 2020 – First vaccine clinical trials begin in U.S. (National Institute of Allergy and Infectious Diseases (NIAID) and Moderna (biotechnology company in Cambridge, MA) – “launched in record speed,” 66 days from genetic sequencing of virus to the first human injection of the vaccine candidate.
18 March, 2020 – Deaths in Italy surpass those in China.
19 March, 2020 – No new cases confirmed in Hubei,
25 March, 2020 – Retrospective studies in Lombardy confirm that the virus was present in Northern Italy in early January
1 April, 2020 – Over 80% of ICU patients with COVID-19 have underlying medical conditions.
2 April, 2020 – Worldwide cases surpass 1,000,000.
7 April, 2020 – No new reported COVID-19 deaths in China
8 April, 2020 – Tracking App reveals lack of smell is key symptom.
15 April, 2020 – Trump – in his infinite wisdom and trust-worthy scientific knowledge – suspends WHO funding. Leonardo Da Vinci’s birthday celebrated by “scapegoating” the WHO.
15 April, 2020 – Worldwide infections surpass 2,000,000.
21 April, 2020 – Mars probe HOPE ships from UAE to Japan for launch after July 15^th when Mars and Earth are aligned. It should reach the Red Planet by 2021.
21 April, 2020 – https://1daysooner.org/volunteer 15,000 people volunteer to be exposed to virus and accelerate vaccine development.
27 April, 2020 – The five ways Trump is undermining environmental protection under the cover of the Pandemic: https://nature.com/articles/d41586-020-01261-4
29 April, 2020 – Remdesivir speeds up recovery!
7 May, 2020 – First CRISPR testing kit approved in US. It works by programming the CRISPR machinery to detect snippets of the virus genetic material and expedites results to 1 hour.
15 July, 2020 – Only medications with proven efficacy so far: Remdesivir (antiviral) and dexamethasone, when used in patients with pneumonitis seems to expedite recovery, but not early on. In fact, it may worsen outcomes when used at the outset of disease. Non- Invasive oxygen delivery may be associated with better
16 July, 2020 – mRNA vaccine able to generate adequate immunogenic responses and phase III clinical trial to begin soon.
20 July, 2020 – Recombinant Adenovirus vaccine that encodes SARS- CoV2 Spike protein is highly immunogenic on phase I/II clinical trials conducted in the UK and phase III trials to start
27 September, 2020 – Over 33,000,000 cases and almost 1,000,000 deaths Over 7,000,000 cases in the US and 205,000 deaths. Pandemic tracker: https://coronavirus.jhu.edu/map.html
9 November 2020 – Pfizer – Bio-N-Tech vaccine reported preliminary efficacy of over 90% and buoying humanity (and the markets) into It requires two sequential injections
10 December 2020 – Pfizer/Bio-N-Tech mRNA vaccine approved and deployed initially in Great Britain and US.
15 November 2020 – The US reaches 11 million cases and almost 250,000 deaths.
15 December 2020 – The US reaches 17 million cases and almost 310,000 deaths. Worldwide, over 74 million cases and 1.7 million
December 2020 – B.1.1.7 variant emerged in Britain, found to be roughly 50% more infectious. Now detected in more than 70 nations.
Late December 2020 – B.1.351 variant appears in South Africa which decreases the efficacy of AZ vaccine by 20%.
Late December 2020 – P1 variant detected in Brazil
7 Feb 2021 – B.1.1.7 variant is doubling every 10 days in the US
11 Feb 2021- Illinois confirms first case of 1.351 variant.
15 February 2021 – 28 Million confirmed cases in the US and almost 500,000 deaths.
30 March 2021 – 130 Million cases worldwide and almost 3 million