August 30th, 2021

My current recommendations continue: 1) get vaccinated and take the guess work out of this as this dramatically reduces death and hospitalization risk. 2) follow the links in the introduction above for an integrative approach to remaining immune solvent to reduce all cause infectious mortality risk. 3) live every day like it is your last by honoring your mission to be a great human while you love people around you and while you love yourself.

 It is time to address the elephant in the room again, obesity. We have continued to see the popular press dance around the obesity subject as we normalize the world of inflammatory lifestyle induced disease.

Human appearance is irrelevant only in so much as it is a marker of inflammatory disease risk. Skinny individuals can have the same inflammatory risk based on the same antecedent lifestyle inputs. Therefore, we need to focus on the nutritional and chemical inputs in all humans but not lose sight of the massive death risk that is inflammatory based obesity as it relates to COVID. When I talk to my internal medicine and pediatric colleagues, a few things immediately register for me:

a) the ICU's are now filled with unvaccinated COVID patients while the vaccinated breakthrough cases that make it to the hospital are very rare and mostly there for short periods then end up going home. Death in this group remains rare even with delta and 88% of these deaths are in vaccinated individuals over 65 years old. (per the CDC.) This is first hand knowledge from people with boots on the ground and not anecdotal stories being passed around. Remember that vaccination is not 100% effective but it is vastly vastly superior to not vaccinating.

b) Although we don't have clear data on the comorbid disease of breakthrough cases, the vast majority of admitted patients were inflamed based on risk factors throughout the pandemic and we can assume that this holds true for the breakthrough cases as the age predilection has shown. There are and will be very rare cases of presumably healthy individuals getting sick as has occurred all pandemic long. My friends are telling me that they are seeing more 30 to 50 year olds dying than during the alpha COVID surges. These folks are unvaccinated. Most of them have hypertension and or obesity, but a few are without known co morbid disease.

c) children remain mostly asymptomatic and/or mildly symptomatic. There are more COVID ICU childhood cases purely based on the volume of children infected which is very high right now. We are running between 15 and 25% of tested children being positive which is double the peak over the entire pandemic. We remain at only 3 MIS patients among hundreds and hundreds of cases in our clinic population with zero deaths. We are seeing a ton of cases now with only mild disease or flu like symptoms. US death number for COVID is at 430 since the pandemic began in children from 0-18 years of age. That is 8.6 per state over 20 months. Understand, that these data points are never trivial as death is always tragic for someone. Yet, we must look at this without emotion in order to keep fear and poor decision making in check. Remember that driving a car carries a high risk burden for death yet we continue to do it day in and day out without questioning death. 2375 teenagers alone died in 2019 from driving dwarfing COVID risk.

d) there is zero evidence that the mRNA vaccines cause any hormonal or reproductive concerns despite the undercurrent in the social media world. There are brief changes in menstruation occurring in some females following vaccination and disease as well. These issues are transient and not associated with any known long term issue of reproduction or hormonal health. The reality behind infertility is primarily related to advancing age and poor lifestyle choices that affect hormonal function. If you are worried about yours or your child's hormonal health please plan to listen to the upcoming podcast with Dr. Victoria Maizes. We dive into the reality behind infertility based on the science and not conjecture. She is the Chief, Division of Integrative Medicine and the Executive Director, Andrew Weil Center for Integrative Medicine at the University of Arizona School of Medicine. She authored the book, Be Fruitful, The Guide to Maximizing Fertility and Giving Birth to a Healthy Child. She is brilliant and trustworthy. The answers to the questions of fertility are found during the hour long conversation.

Quick Hits - I am going to focus heavily on B and T cell immunity as a reason to understand what is happening with the mRNA vaccine's mild failure and true booster need.

First off, before we discuss the quick hits, I want to say that the vaccines are not failing so much as they are less effective against the new delta variants mutated spike protein structure. As you will see below, the B and T cell memory is still adequate for viral recognition and then killing in most cases because our immune system is really smart and planned for this(see #4). The lack of complete protein binding affinity has delayed the immune system's response enough for the SARS2 virus to gain a foothold in a subset of the vaccinated individuals leading to higher viral loads and thus symptomatic disease. However, the immune system is catching up and killing SARS2 in most cases based on the hospitalization and death statistics to date. For me, the greatest risk of a problem whether vaccinated or not is whether or not you have a co morbid inflammatory based disease like metabolic syndrome.

1) Redo because of importance and timing with the delta surge and the question of boosters. If you have higher levels of neutralizing antibodies post vaccination and likely by extension post natural illness, your risk of a reinfection is exceedingly low. (Mallapaty R. 2021) Neutralizing antibodies are the antibodies that specifically prevent the virus from attaching to and infecting the cell rendering them non infectious. Thus, these antibodies are critical in the fight against pathogens. In previous studies with previous vaccine related responses, abnormal host microbiomes, stress, and other causes of immune dysregulation can ruin an immune response to a vaccination. (de Jong et. al. 2020)(Kiecolt-Glaser J. 2021)

The new discussion around boosters and breakthroughs really need to be targeted in populations based on SARS2 antibody responses over time. If you had a poor vaccine response the first time around or post natural illness, then a booster makes a lot of sense to prevent illness. Remember that death and hospitalization are still exceedingly rare regardless of boosting. The kicker yet remains the elephant in the room as discussed above. If you are prone to inflammation based on your persistent poor lifestyle choices of SAD American type foods, chemical exposure, sloth, sleep deprivation and so on, then you will be at higher risk for hospitalization and maybe even death in a post infection/vaccination breakthrough case.

If you do decide to get boosted when the boosters come around in the next month, then, as always it behooves you to sleep well and consistently around the period of vaccination. We should maintain an anti-inflammatory diet type to limit nutritional stressors and micronutrient insufficiencies that can sack your immune response. We absolutely should work on our innate stress and response to it. Esentially, following the same rules of healthy living to prevent covid from killing us also help us respond well to the vaccine.

 

2) The Delta variant has made the Pfizer vaccine fair poorly against full infection prevention but remains high quality against hospitalization and death. Israel is the perfect incubator of our future as they are months ahead of us on all metrics of vaccination, response and variant change. They also used the mRNA Pfizer vaccine across the country. In Israel, the length of time from the vaccination was directly correlated to breakthrough infections indicating waning antibody based immunity over time. Vaccinees from January were 2 times more likely to have a breakthrough infection than those from April. (Mizrahi et. al. 2021) They also have noted that breakthrough outcomes are highly correlative to age and co-morbid disease association. From the Clinical Microbiology and Infection study, "A total of 152 patients were included, accounting for half of hospitalized fully vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notably, the cohort was characterized by a high rate of co-morbidities predisposing to severe COVID-19, including hypertension (108; 71%), diabetes (73; 48%), congestive heart failure (41; 27%), chronic kidney and lung diseases (37; 24% each), dementia (29; 19%) and cancer (36; 24%), and only six (4%) had no co-morbidities. Sixty (40%) of the patients were immunocompromised. Higher viral load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titres of anti-Spike IgG, but these differences did not reach statistical significance." (Brosh-Nissamov et. al. 2021)

Breaking it all down. We do not have any good US data regarding breakthroughs to date. Our local hospitals are telling me that most cases are unvaccinated and the vaccinated cohort is mostly not severe but some have required hospitalization. Death remains rare but the co-morbidities seem to still play a major role in a negative outcome when vaccinated as in the unvaccinated. This is almost entirely do to the base line inflammatory state of the human immune system.

We also know that cases are worse when a person has low circulating antibodies against SARS2 and also develop high viral loads. Reasons for a poor vaccine or natural infection antibody response are likely predominantly based on immune suppression or poor antigenic response which is known to happen in obese individuals and those with a dysfunctional intestinal microbiome. As we noted last year, there is also a subset of men with autoimmune antibodies against gamma interferon reducing viral killing capacity which can further worsen the viral load expansion. Once again, we sit in a control what you can control situation.

3) Delta as we are seeing is a major contagious nightmare that is now more transmissible that Smallpox, Influenza, Sars1/Mers1 and on par/slightly less than with Chicken pox. Only Measles is a worse train wreck infectiousness wise. The R0, reproduction rate, for these infections is 1-2 for influenza meaning for every 1 infected person,1 to 2 others will be infected. For Sars2 alpha that number was 3. Now SARS2 delta is at around a 6. Chicken pox is a 10 and measles is a 12+. Therefore, for SARS2 delta for every infected person, 6 will be infected. Then those 6 will infect 6 more and on and on. This is exponential and explains why a R0 of 2 is nowhere close to the infectiousness of a 6 and way less than a 12. Here is how it looks numerically:
1 infected person with: flu infects 2, SARS2 alpha 3, SARS2 delta 6, Chicken pox 10 and Measles 12.
then those infected people with: flu infect 4, SARS2 alpha 9, SARS2 delta 36, Chicken pox 100 and Measles 144.
then those infected people with: flu infect 8, SARS2 alpha 27, SARS2 delta 216, Chicken pox 1000 and Measles 1728.
then those infected people with: flu infect 16, SARS2 alpha 81, SARS2 delta 1296, Chicken pox 10000 and Measles 20736.

These numbers are sobering! The variant jump in infectiousness for the alpha and delta variants goes from 81 to 1296 cases by the end of four events. That is a wildfire.

4) Let us take a deeper dive into the technical world of B cell memory and therefore lasting protection post vaccine or natural illness. Once you have seen the virus' RNA protein fragment as either a spike fragment from the mRNA vaccine or chopped up portions of the natural virus, your immune system will present this sequence to the B cell in an elegant way called antigen presentation that will develop a subspecies of B cell called the Memory B cell which has the distinctive ability to be quiescent and long lived in our bone marrow after the SARS2 virus is dead and gone. The entire purpose of the long lived memory B cell is to have the ability to re recognize the SARS2 virus when it returns. The rapid RNA sequence recognition based on this memory allows for the immediate development of neutralizing antibodies that squash the SARS2 virus rapidly next time around.

What about the variants? We know that the SARS2 virus mutates at a modest pace. If the SARS2 RNA has changed its structure during a mutation, let's say from alpha to delta, does the memory B cell still have immune ability or do we lose immune recognition? Here comes the beauty of the human immune system.

Do you remember the stories of people getting super swollen lymph nodes in the armpit of the vaccinated arm? This was a sign that the T and B cells were migrating to the local lymph nodes of the armpit to exchange genetic viral information in preparation for memory B cell development. In the germinal center of these lymph nodes, the antigenic material (protein fragment of the virus) is exchanged and understood immunologically. One fate of this activity is critical. These B cells will go through divisions deeper in the germinal center of the lymph node (think of the rings on a tree moving closer to the center). With each division the B cell adds a mutation to the B cell receptor which mirrors the virus with minor alterations in the anticipation that the virus will mutate as well.

Think about this. Our immune systems evolution coincided with the knowledge that pathogens mutate over time so we do the same thing. The process is called somatic hypermutation whereby the B cells have affinity maturation that allow them to specialize to viral or pathogen structures for future recognition. There are two different types that predominate over time. The basic memory B cell which has a poly reactive memory to a pathogen allows for a lot of flexibility in case of pathogen mutation. The long lived plasma cell is a more high affinity B cell that has more tightly bound antigen recognition and therefore aggressive antibody targeting to a specific previously seen virus.

Memory B cells hide in the tonsils, lymph nodes, spleen , bone marrow and in the blood stream plotting there next attack like a hiding snake in the off chance that a SARS2 (pick your greek letter) mutation variant comes to play. The human B cell variants are ready and poised to get a head start at the viral killing game.

It is a beautiful thing and the major reason behind my belief that we are ok over time with SARS2 if we are either vaccinated or had natural disease and are practicing high quality living that reduces the big four co-morbid diseases. This leads to #7 below from Monika Ghandi.

5) Repeat again with added sections based on relevance to the booster discussion and importance: A few people are asking about the need to vaccinate if you have already had COVID natural illness. What is the story here? Hot off of the press from Cell Reports Medicine, we see: "Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients." (Cohen et. al. 2021)

This builds upon other studies finding very good long term memory B and T cell responses after natural infection especially with increasing severity of the natural illness. This means that in most cases, you are well protected from COVID after a natural infection. However, some RARE individuals will have a low antibody response and may also mount a weaker immune response the second time around as has been shown in some cases. Predicting who these individuals are is not possible at this time on a population basis. Thus, there is a reasonable argument for COVID naturally infected individuals to get one booster dose of an mRNA vaccine to insure a quality response immunologically upon preexposure to the virus. I cannot find any reasonable data or reason to get a two dose series in these people. (Krammer F. et. al. 2021)(Saadat et. al. 2021)(Abu Jamal et. al. 2021) More on the "Do you need a second vaccine dose" if you know that you had COVID already naturally? Now we have a longitudinal study that also finds that the second dose has no added benefit for those persons in the convalescent phase of SARS2. They looked specifically at the T cell response and found that: "Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity but not quality of the T cell response, while in convalescents the second dose helped neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx." (Neidleman et. al. 2021)

If you had natural infection and received one dose of a COVID vaccine, the T cell function and by definition your outcome if re-exposed again looks great. Thus, it makes logical sense now to prioritize vaccinating the global population with appropriate doses based on known convalescent history.

6) Evolution of the SARS2 coronavirus may have reached a perfect level of fitness with the delta variant. It is incredibly effective at transmission while not being more deadly than alpha. Time will ultimately tell if it evolves again in a significant way. If you think of the evolution of humanity with respect to SARS2/Covid19 risk, it is clear to me that this virus would have been much less deadly 30 or 50 or 100 years ago before the invention of modern processed foods, chemicals and stress that have upended human immune health and lead to an era of metabolic diseases and immune dysfunction. I have thought about this for some time and the reality is as such. We are here to some extent by our own doing and that is a tragedy of our time. Remember that 96+% of all deaths are based on lifestyle induced diseases of chronic overindulgence of food, sloth and chemical exposure.

Some may say that modern medicine is saving countless lives and that is so, but how many would have never entered the hospital based on much better baseline health and therefore not be in need of an ICU or a ventilator at all? Ah, these are questions that we cannot answer less we just hypothesize.

However, the thought that we need boosters now is an interesting one and I am not lining up with this yet for two reasons: 1) do we have robust safety data on three vaccines in a calendar year. I have not seen any and 2) why do we now think that vaccinated and naturally infected people cannot mount a robust response to the delta variant moving forward to prevent a negative outcome based on the T and B cell data coupled to current vaccinated persons reinfection outcome risk?

Let us explore these. #1 is self explanatory, until we have safety data that is robust, I will hold at two mRNA doses and take my chances with natural infection while practicing incredible self care for robust immune solvency. #2 is a bit more tricky.

We know that we are likely developing excellent B and T cell responses to natural immunity and vaccination that confer an early warning signal and protection against the return of SARS2. The B cells have memory to the SARS2 virus and upon re seeing it, they will begin to pump out tons of antibodies via plasma cells in rapid fashion reducing the risk of a negative outcome. The T cells are primed and ready to kill any cell tagged with a fragment of the virus' protein structure making quick work of the virus and preventing a significant negative outcome.

If this virus is now endemic, which it likely is as it has animal reservoirs and a mild lethality(compared to SARS1/MERS/ebola, etc..) with a prodrome of infectious spread pre symptom, then we are likely to be living with this illness forever. Eradication through vaccination is highly unlikely as we have seen happen with MMR and smallpox. Do we plan to boost ourselves biannually? Is that safe? Or, should we really look at this as we do with influenza, whereby the at risk population is most impressed upon to vaccinate at the recommended schedule while everyone else practices quality self care?

Lots of questions without much data to make a good decision on. We need more safety data and booster need data to be more educated in this decision. There is some rationale to boosting without robust safety data if you are in a high risk pool like the over 65 year old group, or people with one of the big four comorbid metabolic diseases.

7) I like this 7 reason list for why boosters are unlikely to be necessary. Monika Ghandi is an Infectious Disease specialist at UCSF in California and a well read author published this list in Mashup MD.
REASON #1: Memory B Cells Are Produced By Vaccines and Natural Infection
REASON #2: Memory B Cells Can Produce Neutralizing Antibodies If They See Infection Again Decades Later
REASON #3: Vaccines or Natural Infection Trigger Strong Memory T Cell Immunity
REASON #4: T Cell Immunity Following Vaccinations for Other Infections Is Long-Lasting
REASON #5: T Cell Immunity to Related Coronaviruses That Caused Severe Disease is Long-Lasting
REASON #6: T Cell Responses from Vaccination and Natural Infection With the Ancestral Strain of COVID-19 Are Robust Against Variants
REASON #7: Coronaviruses Don't Mutate Quickly Like Influenza, Which Requires Annual Booster Shots

I could not agree more with her. We need to be thinking these issues through logically and without emotion.

Keep dancing,

 

Dr. M

Mallapaty Nature News
de Jong Cell Host Microbe
Kiecolt-Glaser OSU Medical School
Bergwerk NEJM
Marshall Nature News
Mizrahi MedRxIV
Brosh-Nissamov Clin Microbial Infect
Cohen Cell Reports Medicine
Krammer NEJM
Saadat JAMANetwork
Abu Jabal Euro Surveill
Neidleman MedRxIV
Palm Frontiers in Immunology
Li Virological
Jones Wall Street Journal
CDC MMWR
CDC Variants Page

 

National Geographic has a comprehensive article on the delta variant. LINK