January 17th, 2022

Ugh - 2 weeks changes everything

My partner, Dr. Koontz stated the other day, that nature is vaccinating the US with Omicron since we couldn't do it. He was present during measles outbreaks in Dallas, Texas during his training and he noted this feels closer to that than anything in his career. He is correct. Everyone will see this virus sooner or later this year. Hopefully, since we cannot vaccinate this virus into submission like measles, this will become like seasonal influenza where we have some a priori immunity leading to less death. Fingers crossed.

Last Covid newsletter: "Omicron is highly transmissible and cruising throughout the country especially in the colder states. We are at the highest daily case rate since the pandemic started. This week - 486,000 + cases in a single day. The case number is actually much higher due to uncounted positive at home tests. However, the blessing is that death and hospitalization rates are not following at all. Therefore, we need to keep our focus on hospitalization and not case number." This is no longer true!

Some expected this mess with hospitalization, I did not. Between reports from South Africa and Europe, I expected many cases but minimal to moderate hospital needs. Yes, it is mostly mild, however, with such insane volumes of infected persons, we are seeing a large cohort of unvaccinated and vaccine waned individuals getting admitted to the hospital. This truly is now threatening some hospitals and that is very unfortunate. These hospital numbers were not seen in South Africa or other countries. I am humbled. I believe this to be a marker of two issues: 1) Relative level of poor health in the US 2) level of citizens that are unvaccinated and without previous moderate natural infection.

Boost? My original thought was that there is no obvious need anymore with the current vaccines failing to protect against omicron infection and the benefit of a natural infection or vaccine induced immunity against hospitalization and death in general. However, at this scale of illness, the booster may lower morbidity and case volume somewhat which could help the hospitals, although this is speculation. The vaccines are still incredibly valuable to prevent death if one is completely unvaccinated or vaccinated with risk factors. Omicron is still hospitalizing the vaccinated and at risk groups primarily- advanced age, immune compromised, obese, hypertensive, diabetic and with heart disease. However, the unvaccinated groups are at the highest risk. My friends in the hospitals tell me that the cases in the ICU are all unvaccinated. Thus, if you are unvaccinated and not previously infected, you have a significant risk of death. Please vaccinate.

Omicron is spreading like chicken pox with a reproductive rate of greater than 8 and cruising throughout the country almost everywhere. For every one person infected, they infect 8 who infect 64 who infect 4096 who infect 32768 and on - yikes. We are at the highest daily case rate since the pandemic started. This week over 800,000 + cases in a single day. The case number remains actually much higher due to uncounted positive at home tests. We are possibly heading towards a version of herd immunity based on this epic volume of disease which appears to have possibly happened in South Africa and now England. We are already seeing declines in case number in many major cities like NYC. However, the blessing is that while hospitalization rates are rising rapidly they are not associated with the same volume of death, yet, based on the countries 68.5% double dose vaccine status and natural T and B cell immune memory to a previous natural infection. By the numbers, 31.5% of 330 million is still 104 million people at risk for a bad outcome due to being unvaccinated. If we assume a death rate of 0.5% based on modern medicines/treatments (a guesstimate), then we will see 520,000 more deaths if all get infected this time around. Vaccines could prevent most of these deaths.

We know that the vaccines are no longer working well to prevent transmission of SARS2 Omicron. This was expected based on the mutations in the spike protein as discussed in the past 2 weeks. This is abundantly clear in your local environment and from the reams of case data. Boosters are offering no major protection that I can see visibly, but this may not be true on the population level according to the experts. I have many friends and colleagues that have been infected despite 3 shots of an mRNA vaccine. The good news remains that the vaccines prevent most bad outcomes which is really important and offer milder disease when infected.

Based on how surprising the last 2 week shift in hospital volume is, I reached out to Dr. Danny Benjmain for comment.

Answers to booster questions with Dr. Benjamin:

"There is a big difference in boosters

1)     Across age strata, it is estimated (as of January 1, 2022) that 2 shots provide approximately 30% reduction in infection with omicron. 3 shots provide substantially more protection to prevent infection, with some indication that such protection might be as high as 80% in the first 12 weeks after boosting. Given the number of infections in Americans every day and what is going to happen to hospitals in 1-2 weeks, this is important

2)     Yes, omicron is less severe. But math is hard. If there is 30% reduction in severity, and you have 10 times as many cases, the hospitals will be in worse shape than this time last year. So item number one for people at near zero risk of hospitalization is important even if all it does is delay infection until march or april (where the super charge effect of boosters on infection will likely start to subside)

3)     Boosters also make a big difference in hospitalization on the population scale. Even if there is only a 10% relative reduction in hospitalization with booster for omicron, when the impact is on 300,000,000 people, that is a big get.

Finally, quality of life. If you prefer to suffer with your covid infection, limit yourself to 2 doses. if you prefer an asymptomatic (or minimally symptom course) get a booster. "

Dr. Danny Benjamin

A flip side opinion written by Dr. Vinay Prasad is also worth your time.

"Putting these 3 studies together: what is the conclusion? Two doses of vaccine does nothing or almost nothing to stop symptomatic sars-cov-2. Three doses barely does anything, and the effect will likely attenuate over time. Finally, as the number of exposures increase from 2 to 22 to 202, the cumulative probability of infection will approach 1. NOTE: This is not an argument about the benefits of vaccination for the individual— vaccines likely (and evidence shows they) still have great protection against severe disease; instead this is an argument about the effects of vaccination on symptomatic diseases, and (some good portion of) transmission.

Conclusion: you cannot contain the viral spread of omicron by boosting. Booster mandates make no sense for young people/ working people/ hospitals/ anywhere. Young people will only be, at best, slightly less likely to spread for a short period of time, but the epidemic waves will eventually over take them. Boosting should happen in populations where it further reduces severe disease and death— aka older & vulnerable people. Focus on that and let college kids off the hook." (Prasad V. 2022)

As always, I try to provide multiple views to the questions at hand.

See the quick hits for more on this whole booster or not issue.

We are hopefully hurtling toward herd immunity on some level. We are testing many and 50% are positive in our clinic with this weeks reporting numbers. Therefore, we are going to see everyone get infected at some point this year. We may and probably will hit the 90% required infected level to be at some form of herd immune blockade. The price may be high for the unvaccinated and that is tragic. We are still absolutely in a different world now with this milder variant coupled to a mostly non SARS2 naive population that has robust T and B cell memory with which to tackle the viral variants. I restate that the big issue now appears to be that the Omicron variant is still affecting the unvaccinated in a significantly negative way. This was somewhat unexpected based on reports from other countries.

Last week, I stated that unless some unimaginable change occurs via a novel mutation or some unforeseen event, we should be heading in the right direction for a normal life with COVID now. This may still hold true after the pain of this massive wave burns out. Covid is endemic now. It is here to stay. Hopefully, it will continue to become less deadly over time.

Omicron's infectiousness is putting a massive strain on the healthcare system due to the lack of health care based workers on the job who are ill coupled to the unexpected volume of hospital admissions. With so many people testing positive and needing to quarantine from work, we are struggling to keep effective workflows and production that could have serious consequences in the hospital and clinic setting for all cause illness, not just Covid.

Last week, I said: "hopefully, the lack of severity will balance this equation. Time will tell, but so far so good." - this is unfortunately wrong as we have discussed. Too much illness to have a balanced equation it seems.

On a different note: Again, seeing the mess in Chicago, please do not close any schools unless we shut down the whole country, which we shouldn't do either. We cannot have professional sports, restaurants and bars open while kids zoom to learn. Nope. This disease is now a part of our lives. We need to make the necessary adjustments each and every time a variant occurs and life gets tricky. Let's roll up our sleeves again and become hardworking citizens of this great nation. Teachers teach, healthcare providers care, front line workers do what they do best and all the way down the line.

At this point, if you are vaccinated, your risk of death is very very small unless you are very very unhealthy. See number 4 below.

New CDC guidelines: People with COVID-19 should isolate for 5 days and if they are asymptomatic or their symptoms are resolving (without fever for 24 hours), follow that by 5 days of wearing a mask when around others to minimize the risk of infecting people they encounter. The change is motivated by science demonstrating that the majority of SARS-CoV-2 transmission occurs early in the course of illness, generally in the 1-2 days prior to onset of symptoms and the 2-3 days after. - This is a very welcome admission of change in the face of good science that has been around for a while.

Quick Hits -

1) According to a study from Kaiser Permanente, the risk of death from Omicron is 91% less than Delta. The authors state: Our analyses included 52,297 cases with SGTF (Omicron) and 16,982 cases with non-SGTF (Delta [B.1.617.2]) infections, respectively. Hospital admissions occurred among 235 (0.5%) and 222 (1.3%) of cases with Omicron and Delta variant infections, respectively. Among cases first tested in outpatient settings, the adjusted hazard ratios for any subsequent hospital admission and symptomatic hospital admission associated with Omicron variant infection were 0.48 (0.36-0.64) and 0.47 (0.35-0.62), respectively. Rates of ICU admission and mortality after an outpatient positive test were 0.26 (0.10-0.73) and 0.09 (0.01-0.75) fold as high among cases with Omicron variant infection as compared to cases with Delta variant infection. Zero cases with Omicron variant infection received mechanical ventilation, as compared to 11 cases with Delta variant infections throughout the period of follow-up. Median duration of hospital stay was 3.4 (2.8-4.1) days shorter for hospitalized cases with Omicron variant infections as compared to hospitalized patients with Delta variant infections, reflecting a 69.6% (64.0-74.5%) reduction in hospital length of stay. (Lewnard et. al. 2022)

The study also noted 74% less ICU care needed and 54% less hospitalization. The reason behind these changes seems to be related to the mutations that made the Omicron variant more likely to infect the upper lung tissue and the nasopharynx leading to less tissue damage in the terminal lung tissue where oxygen and blood are exchanged. This appears to lead to less inflammation and downstream damage systemically. This is all good news overall.

2) "Highly transmissible SARS-CoV-2 Omicron variant has posted a new crisis for COVID-19 pandemic control. Within a month, Omicron is dominating over Delta variant in several countries probably due to immune evasion. It remains unclear whether vaccine-induced memory responses can be recalled by Omicron infection. Here, we investigated host immune responses in the first vaccine-breakthrough case of Omicron infection in Hong Kong. We found that the breakthrough infection rapidly recruited potent cross-reactive broad neutralizing antibodies (bNAbs) against current VOCs, including Alpha, Beta, Gamma, Delta and Omicron, from unmeasurable IC50 values to mean 1:2929 at around 9-12 days, which were higher than the mean peak IC50 values of BioNTech-vaccinees. Cross-reactive spike- and nucleocapsid-specific CD4 and CD8 T cell responses were detected. Similar results were also obtained in the second vaccine-breakthrough case of Omicron infection. Our preliminary findings may have timely implications to booster vaccine optimization and preventive strategies of pandemic control." (Zhou et. al. 2021)

This basically is stating that if you get natural infection with variant omicron after being immunized, you will have an excellent immune response which is better than the original immunization. These study results tell us that Omicron evaded the Pfizer vaccine, but the natural breakthrough infection elicited an excellent level of cross-reactive neutralizing antibodies against all of the circulating variants of concern, not just omicron. This is fantastic news. Omicron is mild and natural infection is providing us excellent immunity against all variants. Another reason to question the booster decision unless you are in the high risk category. Again, this data is presented in order to give you a choice regarding boosters.

3) Being exposed to the other 4 circulating common cold coronaviruses offers immunologic cross coverage against Delta and Omicron. This is especially common among parents and workers around children aged 0-5 years old. Teachers, daycare workers, pediatricians are in this category. We get exposed to everything and benefit in the long run. (Kundu et. al. 2022) This may be a window into future vaccines that have other cross reactive proteins on board to expand the immune response.

4) "Our results indicate that systematic surveillance of asymptomatic vaccinated HCWs uncovers many times more cases of Vaccine Break Throughs or VBT infection than symptom-based testing. The incidence of asymptomatic VBT infections seemed to depend on the frequency of testing and not occupational risk or community prevalence; once corrected for frequency of testing, incidence was similar in the high- and moderate-risk groups. Asymptomatic cases seemed to clear much more quickly and had higher mean antibody levels than symptomatic cases. Because of the rapid viral clearance in asymptomatic VBT infections, our surveillance program likely missed many other such infections."(Novazzi et. al. 2021)

This study was performed with delta as the prominent variant. If you look for it routinely, you will find more cases, but that is almost assuredly unrelated to significant transmission as the asymptomatic cases are associated with a faster clearance of viral particles in the tissue. This is very different than super spreaders and ill people in general. Asymptomatic cases are not the problem and never have been in children who are low risk spreaders. We need to steer away from this testing metric especially in schools. Symptomatic testing remains the route of Omicron discovery and quarantine protocol. Avoid the desire to test everyone in schools as you will likely find a lot of asymptomatic cases that are not causing disease spread. The removal of a child from school for a positive test is not fruitful but will continue as long as we keep testing non ill people.

Imagine that you can get this infection 2-3 x a year just like a common cold for the foreseeable future. Are we going to keep these children, their siblings and parents quarantined every time from now on for each true asymptomatic case and the false positive cases. That is an unbelievable volume of missed school, work and life in general. We need to focus on illness and spread risk first and foremost. In other words, we need to get busy living with this virus. If you choose to remain unvaccinated and or have unhealthy habits putting you at increased risk over time, then you have a chosen a riskier path and that choice is yours and yours alone.

There remains a huge volume of unvaccinated children nationally for many reasons. Unvaccinated children cannot be blamed for an adults outcome. The kids are not the problem. Unvaccinated and unhealthy people are driving the hospital dilemma. I am not judging these people as they have a right to choose there path. I am merely stating that children are not the issue anywhere in this pandemic and they have suffered based on fear.

5) From MMWR: Among 1,228,664 persons who completed primary vaccination during December 2020–October 2021, severe COVID-19–associated outcomes (0.015%) or death (0.0033%) were rare. Risk factors for severe outcomes included age ≥65 years, immunosuppressed, and six other underlying conditions. All persons with severe outcomes had at least one risk factor; 78% of persons who died had at least four.

If you had a primary 2 dose vaccine series against SARS2, you have a 0.0033% chance of dying or 0.000033 which is 33 in 100,000 cases. If you add in the age and underlying comorbid disease risk, most of us have zero risk of dying. This data set is earily similar to initial data at the beginning of the pandemic. Age and comorbid disease is the route to a bad outcome in almost all cases. This data was all Delta variant related which means that the numbers are orders of magnitude smaller for Omicron. Keep it all in perspective.

Thus, again we sit here with data points for booster decisions. To vaccinate with boosters that are minimally effective against Omicron is a personal choice that is highly recommended by the medical community to protect the unvaccinated, the immune suppressed and the genetically at risk.

6) In a paper in the Atlantic, we see an interesting discussion about the change in attitudes by people regarding the Omicron variant and their desires to follow current guidelines and or practice mitigating measures, i.e. pandemic fatigue. (Thompson D. 2021) People are tired of the pandemic, the misinformation, the political involvement and the general stress that comes along with all of the above.

7) If you received a covid vaccine, the longer the time interval between the vaccine and a breakthrough infection was associated with better long term immunity. It appears that the later breakthrough infection occurs when the antibodies circulating against covid have waned significantly leading to the response to come from the memory long lived plasma cells. This also allows for a robust retraining through the lymph nodes germinal centers where antibody variations can occur to mimic the viral mutations.

From the article:"“It’s an interesting study,” says immunologist Jenna Guthmiller at the University of Chicago in Illinois. She cautions that the results are solely correlative, but adds that they are in line with immunologists’ general understanding of how antibody responses mature over time. Guthmiller explains that vaccination leads to an emergency blast of antibody production, as a natural infection would. If a person gets infected soon after vaccination, these antibodies are probably still circulating in the blood, where they’ll bind to the virus and quickly eliminate it. But when a person becomes infected months after vaccination, the antibodies that respond come from a new and improved batch made by long-lived cells that carry a memory of the pathogen. When the body encounters the pathogen again, these memory cells are called back to duty and have a chance to refine the antibodies, providing better protection against subsequent infections."(Sidik S. 2022)

This may be the exact mechanism behind the data showing that spacing out the vaccine interval was associated with better immune responses over time. Thus, if you had a Covid infection or vaccine recently, your immune response will be correspondingly less robust to generate new protective variant antibodies to the new variant exposure. I.e. if you recently had a vaccine and get Omicron within weeks, you will not get significant symptoms, but you will also not have a great long term immune response. My take on this data is hypothetical in that if you have a booster recently and then see Omicron, you will have minimal to no symptoms but will also have a weaker long term benefit. Therefore, will you need frequent boosters in the absence of natural infection? I think so. If the vaccine wanes in 3 to 4 months normally, then you will be set up for recurrent need. If you have a 0.0033% chance of dying once vaccinated, maybe it makes more sense to obtain natural disease if you are young and or older with no risk factors. Thinking out loud.

8) Do you need a fourth vaccine dose? Fourth doses are being used in multiple countries for the immunocompromised and has shown a 5X increase in antibodies after a few weeks. "The rationale for these policies is supported by a range of evidence, including from the UK based Octave (Observational Cohort Trial T Cells Antibodies and Vaccine Efficacy in SARS-CoV-2) study, which found that four in 10 people who were clinically vulnerable generated lower concentrations of antibodies than healthy recipients after two doses of a covid-19 vaccine." (Lacobucci et. al. 2022) Many immunocompromised individuals struggle to respond to the normal 2 or 3 dose series prompting the additional dose or doses as time goes on.

9) Omicron can be missed by rapid antigen tests early in the illness according to some new data in a very small study. (Herper M 2022) PCR remains the only very reliable determinant test of COVID infections. Positive antigen tests in symptomatic persons remains very useful.

10) We need a study looking at the level and length of antibody activity post natural infection versus vaccination and/or booster. It really is time to compare whether boosters are necessary once vaccinated with two doses. I suspect that for those that are healthy and under 65 years of age, natural infection after 2 dose vaccine series will have better and longer lasting immunity than serial boosting. Time and a quality study could help us by answering this question.

11) "Myocarditis is a rare adverse event following COVID-19 vaccination, most often affecting males younger than 30. Although vaccine-associated myocarditis appears to be significantly less common than COVID-19–associated myocarditis (NEJM JW Cardiol Jul 2021 and JAMA Cardiol 2021 May 27; [e-pub]), coverage in the lay press has fueled vaccine hesitancy. Truong et al retrospectively collected data on 139 adolescents and young adults who experienced myocarditis within 30 days of COVID-19 vaccination at 26 centers in the U.S. and Canada (median age, 15.8 years, 90.6% male, 66.2% white, 20.9% Hispanic). In all, 136 of 139 cases occurred after mRNA vaccination, with 131 following the Pfizer/BioNTech vaccine; 128 occurred after the second dose. Symptoms began a median 2 days after vaccination, with chest pain being almost ubiquitous. Most patients received NSAIDs; other treatment options included IVIG, glucocorticoids, and colchicine. Median length of hospital stay was 2 days (range, 0–10 days); 26 patients required ICU care, 2 required inotropic/vasoactive support, and none required ECMO or died. All had elevated troponin, 97 had EKG abnormalities, and 7 had non-sustained ventricular tachycardia. Ejection fraction <55% was seen in 26 patients, all of whom showed normalized ejection fraction on follow-up echocardiograms. Gadolinium enhancement and myocardial edema were seen in most of those undergoing cardiac MRI a median 5 days from symptom onset." (Sakoulas G. 2022) This data set is reassuring for vaccinated teens and young men. Remember that myocarditis following natural Covid infection was much more frequent.

Happy 2022,

Dr. M

Lewnard MedRxIV

Prasad Substack

Zhou MedRx IV

Kundu Nature Communications

Novazzi Annals Internal Med

Yek MMWR

Thompson The Atlantic

Sidik Nature

Lacobucci BMJ

Herper STATNews

Sakoulas NEJMWatch

CDC MMWR

CDC Variants Page