Volume 12, Letter 23 Coronavirus Update 62 plus other stuff

Omicron US strains: newer variant BA.2 makes up 51% of current case volume based on different parts of the country while omicron BA 1.1 is at 1% and B 2.12.1 is 48%. Delta and BA 1.1.529 are now gone by competition. Cases are increasing in some cities with little increase in hospital morbidity and mortality. In essence we are still fairing quite well in the new norm.

Still no major influx of BA.4 and BA.5 in the US. R0 infectiousness is in the range of measles: the new reproductive rate is 1 infects 12 which infects 144 which infects 1,728 which infects 20,736. That is a very fast spread rate.

Little else to report here. (CDC Variants)

All signs point to SARS2-Covid infection 1-3 x per year for most of us moving forward. It is the new common cold with a massive bite. Vaccines and boosters will not slow this train as far as the data shows to date. Lots of data this week.

Quick Hits and other musings -

1) FDA revises the use of Janssen Covid vaccine because of a serious adverse event: After conducting an updated analysis, evaluation and investigation of reported cases, the FDA has determined that the risk of thrombosis with thrombocytopenia syndrome (TTS), a syndrome of rare and potentially life-threatening blood clots in combination with low levels of blood platelets with onset of symptoms approximately one to two weeks following administration of the Janssen COVID-19 Vaccine, warrants limiting the authorized use of the vaccine. (FDA)

Kudos to the FDA for stepping up and giving a strong statement on risk. This decision is important to continue to keep the public aware that the FDA is working to protect all individuals as the science evolves.

2) Let us relook at the MMWR from 1/7/22 by the CDC on the risk of death with Covid. They said: 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. (Yes et. al. 2022)

The diseases associated with severe Covid after 2 doses of mRNA or 1 dose of Janssen were: persons aged ≥65 years, those with cardiac disease, chronic kidney disease, diabetes, immunosuppression, liver disease, neurologic disease and pulmonary disease. Knowing this, this group has to plan for the recurrent exposure to Sars2 over the future decades.

What to do?

a) Get boosted as frequently as possible based on the safety and immunogenicity data

b) Take care of your disease by taking your meds as required for function

c) Eat really healthy to avoid excess inflammation

d) Exercise daily to a light sweat if possible. Movement is key

e) Wear an N95 mask in public spaces, especially indoors

f) Keep micronutrient stores adequate for cellular function including vitamin D, zinc and iron (test w your provider for accuracy)

g) Wash your hands for 20 seconds with soap and water often

h) Sleep 7- 8 hours nightly

i) Test early with any covid like symptoms. If positive, obtain antivirals immediately.

3) More on Boosters from Monika Gandhi: "Another important tool the U.S. should add to its vaccine arsenal is Novavax. Novavax is a protein subunit vaccine, similar to flu vaccines and those for many routine childhood immunizations -- this more traditional vaccine technology could help some overcome vaccine hesitancy. In the U.S., vaccine hesitancy ranges from less than 2% to more than 20% depending on zip code and county. In some states, 14% of those hesitant are concerned about possible side effects and approximately 6% cited "planning to wait and see if it's safe" as of February 2022. Expanding our arsenal to include non-genetic material platform vaccines would go a long way toward addressing these concerns, however unfounded they are. In a phase III trialin adults, two doses of the Novavax vaccine were 90.4% effective against symptomatic infection and 100% effective against moderate and severe disease, although more study in the Delta and Omicron era are needed. Novavax is approved by the WHO and is awaiting U.S. EUA." (Gandhi et. al. 2022)

This is a great idea to reduce the risk that multiple people feel of receiving 3, 4 and 5 mRNA vaccines. Repeated boosting or vaccinating is poorly studied over a longer period of time in a large group to see blips in side effects. This is especially concerning in those at low risk currently for death or moderate to severe disease. The vaccines are not doing much for transmission prevention, thus each person has a reasonable argument to not want to boost in the current situation with current vaccines.

4) Boosters following vaccination are continuing to show weaker immunity against the variants than natural infection after vaccination. Two new studies noted this effect. We have seen these data sets repeatedly show up over the last year. (Ellis R. 2022) Natural immunity for those that are not at risk seems like a better way to go moving forward.

5) "The Omicron variant (B.1.1.529) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) extensively escapes neutralizing antibodies elicited by SARS-CoV-2 infection or vaccination. In the present study, we investigated whether BNT162b2 messenger RNA vaccine-induced memory T cells functionally respond to the Omicron spike protein. Experiments were performed using samples from healthcare workers who were immunized with two or three doses of the BNT162b2 mRNA vaccine and individuals with prior SARS-CoV-2 infection who were immunized with two doses of the BNT162b2 vaccine. Vaccine-induced memory T cells exhibited substantial responses to the Omicron spike protein, with no difference between healthcare workers with two versus three vaccine doses. In individuals with prior infection, two-dose vaccination robustly boosted memory T cells that responded to the Omicron spike protein and the SARS-CoV-2 wild-type (lineage B) spike protein. Importantly, polyfunctionality was preserved in vaccine-induced memory T cells responding to the Omicron spike protein. The present findings indicate that BNT162b2-induced memory T cells substantially respond to the Omicron variant with preserved polyfunctionality." (Jung et. al. 2022)

This study is of interest because the data again shows limited benefit of boosters on outcome risk in a high risk healthcare population. Memory T cells are a major player in severe and moderate disease reduction and there is no difference in these responses whether boosted or not. Boosters appear to only increase your neutralizing antibodies for a very short period of time in multiple studies, as shown in this newsletter in recent months, which in turn reduces the viral illness rate by 50% during the few weeks following injection.

6) Across all age groups, seroprevalence increased from 34% in December 2021 to 58% in February 2022.

The largest increases occurred in children (age range, 0–11; from 44% to 75%) and adolescents (age range, 12–17; from 46% to 74%). By February 2022, three quarters of children and adolescents had been infected with SARS-CoV-2, with about one third of these infections occurring during the Omicron wave. (Ganatra et. al. 2022)

Again, we see that the US volume of children with SARS2 immune knowledge is at a minimum 75%. This raises the question of any need for vaccination for any child with a priori exposure. I have seen no data that it would be necessary moving forward for this group to prevent MIS or any other negative outcome. I am waiting for a cogent argument to vaccinate a child that survived SARS2 without a disease concern. If the child has immune weakness concerns or another disease that makes risk of another SARS2 infection problematic, then vaccines likely make sense. Each person must follow the science and risk stratified data.

7) Deer are now known to be a host for SARS2. A recent publication in BioRxIV shows that transmission back to humans is possible and likely probable but rare. (Pickering et. al. 2022) Per the CDC, there are up to 29 animals that can carry SARS2 making eradication through vaccination impossible. (CDC)

8) More on Boosting. An excellent article by Dr. Paul Offit is worth a full read. Here is a moderate snippet: "What about booster dosing for persons who are younger? One year after the BNT162b2 vaccine became available, studies in the United States showed that a third dose of vaccine also enhanced protection against severe disease for people as young as 18 years of age. Unfortunately, these studies did not stratify patients according to whether they had coexisting conditions. Therefore, it was unclear who among these younger age groups most benefited from an additional dose. Nonetheless, the CDC later recommended that everyone 12 years of age or older should receive three doses of BNT162b2, regardless of whether risk factors were present. This universal booster recommendation led some summer camps, high schools, universities, hospitals, and businesses to require three doses of mRNA vaccine. In February 2022, in a study that did not support the booster recommendation for children, CDC researchers found that two doses of BNT162b2 induced long-lived protection against serious illness in children 12 to 18 years of age.""People are now confused about what it means to be fully vaccinated. It is easy to understand how this could happen. Arguably, the most disappointing error surrounding the use of Covid-19 vaccines was the labeling of mild illnesses or asymptomatic infections after vaccination as “breakthroughs.” As is true for all mucosal vaccines, the goal is to protect against serious illness — to keep people out of the hospital, intensive care unit, and morgue. The term “breakthrough,” which implies failure, created unrealistic expectations and led to the adoption of a zero-tolerance strategy for this virus. If we are to move from pandemic to endemic, at some point we are going to have to accept that vaccination or natural infection or a combination of the two will not offer long-term protection against mild illness. In addition, because boosters are not risk-free, we need to clarify which groups most benefit. For example, boys and men between 16 and 29 years of age are at increased risk for myocarditis caused by mRNA vaccines. And all age groups are at risk for the theoretical problem of an “original antigenic sin” — a decreased ability to respond to a new immunogen because the immune system has locked onto the original immunogen. An example of this phenomenon can be found in a study of nonhuman primates showing that boosting with an omicron-specific variant did not result in higher titers of omicron-specific neutralizing antibodies than did boosting with the ancestral strain. This potential problem could limit our ability to respond to a new variant." (Offit P. 2022)

9) Hospitalization and death remains decoupled from infection volume in the US and now South Africa has published similar data with a population that is less than 50% vaccinated. (Moore et. al. 2022) This tells us that natural infection is leading to immunity that is preventing serious disease the next go round. This is very important. Death and hospitalization is really the metric that matters. Everything else is political theater in my mind.

10) (Technical) From a Nature Communications article that my friend Sam Yanuck shared: "Decline in immune function and inflammation concomitantly develop with ageing. Here we focus on the impact of this inflammatory environment on T cells, and demonstrate that in contrast to successful tumour elimination in young mice, replenishment of tumour-specific CD4+ T cells fails to induce tumour regression in aged hosts. The impaired antitumour effect of CD4+ T cells with their defective Th1 differentiation in an aged environment is restored by interleukin (IL)-6 blockade or IL-6 deficiency. IL-6 blockade also restores the impaired ability of CD4+ T cells to promote CD8+ T-cell-dependent tumour elimination in aged mice, which requires IFN-γ. Furthermore, IL-6-stimulated production of IL-4/IL-21 through c-Maf induction is responsible for impaired Th1 differentiation. IL-6 also contributes to IL-10 production from CD4+ T cells in aged mice, causing attenuated responses of CD8+ T cells. These findings suggest that IL-6 serves as an extrinsic factor counteracting CD4+ T-cell-mediated immunity against tumour in old age." (Tsukamoto et. al. 2015)

Also from Immunity and Aging, "We investigated T cell numbers and differentiation in telomerase-deficient (mTerc−/−) mice under steady-state conditions and the functional role of telomerase in CD4+ T cells using in vitro stimulation and Th1 polarization protocols by comparing T cells from mTerc−/− and control mice. We report reduced relative CD4+ T cell numbers in blood and secondary lymphoid organs and a relative decline in the naïve T cell population in thymus, blood and spleen of mTerc−/− mice compared to control mice. Importantly, after in vitro polarization, mTerc−/− G3 CD4+ T cells showed higher numbers of IFNγ-producing cells and reduced expression of CD28. Notably, telomerase-deficient T cells were more susceptible to inhibition of Th1 polarization by IL-6 in vitro. These results demonstrate that telomerase deficiency recapitulates several changes of CD4+ T cells seen in aged humans regarding the naïve T cell population, expression of CD28 and cytokine production." (Matthe et. al. 2022)

The point of these articles for the non-immunologists (most of us) is that maintaining appropriate viral and tumor killing capacity as we age is dependent on many factors including adequate telomere length as well as limited scope and non chronic inflammation. IL6 is a cell signaling molecule that is very important in many inflammation based processes that are natural for infection and disease resolution. However, in the robust or chronic state, excess IL6 can be very detrimental to our viral and cancer killing capacity. If you look at my white board below, you will see how many lifestyle related factors are driving decreased TH1 and NK cell activity which in turn reduces viral and tumor control. This is increasingly important with advancing age!

11) 400,000 fewer children entered kindergarten in 2021. This issue will add to a large national burden of educational slowing for large volumes of children that already missed school due to the pandemic. It also has concerns for delayed or missing vaccination updates leading to increases in vaccine preventable disease breakthroughs and loss of herd immunity. (Sun et. al. 2022)

That's all this week,

Dr. M

Yek CDC MMWR

Gandhi Medpage Today

Ellis WebMD

Jung Nature Microbiology

Ganatra NEJM

Pickering BioRxIV

Offit NEJM

Moore NEJM

Tsukamoto Nature Communications

Matthe Immunity and Aging

CDC MMWR

CDC Variants Page

Sun WaPo