COVID-19 Weekly Briefing for February 14, 2022
COVID-19 Weekly Briefing for Monday, February 14, 2022, in summary:
New vaccines and antivirals; more stunning information suggesting likely delayed onset health consequences of C19; California to lift indoor masking mandate; case numbers of croup are tied to case numbers of Omicron among children in Seattle; a new smartphone app that detects C19 as accurately as PCR.
The way out of the pandemic is through the nose
I. A new approach to vaccines and vaccination.
The “tweak-and-boost” vaccine model currently used against Scov2 is beginning to look familiar. Each year scientists recommend a different version of the flu shot, meeting in February and September to estimate which strains of influenza virus will be most likely to circulate and gain dominance in the coming 6 to 12 months. The process involves surveillance, genetic sequencing, and predictive modeling and it is less than perfect with effectiveness varying from year to year and rarely exceeding 60% protection against infections. Why? Genetic mutations are random and difficult to predict. By the time the vaccines are built and distributed, the virus has already shape-shifted. In effect, we are always chasing influenza.
However, many viruses that mutate substantially over time nevertheless retain certain portions of their genetic code, generation after generation, variant after variant. Interestingly, these 'conserved epitopes' are consistent between different viruses of the same family. SARS, MERS, and Scov2, for example, are members of the beta coronavirus family, as are OC43 and HKU1 which cause colds–and they all share conserved epitopes.
These conserved epitopes among human beta coronaviruses (HCOVs) provide an opportunity to engineer vaccines that target not only a particular virus or viral lineage but different viruses of the same family all in a single pan-HCOV vaccine.
Building new vaccines that target conserved areas is the first important concept in a strategy to end the C19 pandemic. Why? Targeting conserved epitopes will make immunity from vaccination more durable, protective against many generations of mutated variants and subvariants.
But there is likely to be some trade-off involved in moving from a variant-specific to an HCOV vaccine. The HCOV vaccine will likely be able to induce durable and broad protection against severe illness from any beta coronavirus (including future Scov2 variants) by training T-cells and B cells. But the antibodies they induce will likely not prevent infections very well–especially if the vaccine is delivered intramuscularly (IM). This is the problem we are already seeing with the current vaccines as the antibodies induced by them are having progressively more difficulty recognizing each new variant. Three shots of Pfizer or Moderna vaccine, while >90% protective against developing severe disease (because they trained our B and T cells) are becoming progressively less protective (about 50-60%) against infection with Omicron–something akin to the flu shot.
The second important concept in the strategy to end the C19 pandemic is that IM vaccines are limited in their ability to protect against respiratory and GI infections because they do not engage the mucosal-associated lymphoid tissues (MALT) that surveil and protect the airways and gut, where HCOVs first enter the body.
IM vaccination engages the interior compartment of the immune system which patrols the blood and protects most of the internal organs. But the adaptive immunity induced through IM vaccination remains mostly confined to that compartment. IM vaccination does not induce secretory IgA, the antibody class that attacks the virus at the mucous membranes of the nose, throat, lungs, and intestines.
By contrast, the lymphoid organs of the MALT (tonsils and adenoids in the airways, Peyer's patches in the small intestine) do produce secretory IgA which can pounce on viruses the moment they colonize the airway or gut. In this way, IgA can shut a virus down before it has a chance to penetrate into the body's interior to cause an infection. A vaccine in pill or liquid suspension form or one that is sprayed into the nose could train the MALT against HCOVs to offer more protection against infection.
Pfizer's new IM vaccine tuned to Omicron is projected to be available next month. Moderna is making one too. These are highly specific 'tweak and boost' vaccines that train the body's interior immune system to recognize and attack the new epitopes on Omicron's spike protein. Meanwhile, a new subvariant of Omicron called BA.2 has already emerged to outcompete Omicron.
We should expect that by the time the new vaccine has finished being rolled out, still more highly mutated subvariants or perhaps even an entirely new lineage of Scov2 will have emerged. If the past is prologue, the evolution of Scov2 is unlikely to stop there. Focusing on new variant-specific vaccines will have us chasing Scov2 the way we do influenza with moderately effective results most years.
1439. This week we learn that a single-dose intranasal immunization with chimpanzee adenovector pan-B coronavirus vaccine has been shown in an animal model to be superior to intramuscular immunization in inducing tripartite protective immunity consisting of local (airways and gut) and systemic antibody responses, including production of secretory IgA, mucosal tissue-resident memory T cells, and mucosal trained innate immunity.
Intranasal immunization offers better protection against infections and is effective against both the ancestral strain of Scov2 and subsequent variants (Alpha and Beta were tested so far), indicating that respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation C19 vaccine strategy that could induce all-around mucosal immunity against current and future variants of Scov2 while also offering protection against SARS, MERS, and some viruses that cause common colds.
1440. An uncommon but broadly neutralizing antibody isolated from a convalescent C19 patient has been found to target a conserved epitope on the S2 protein of the Scov2 spike. This conserved epitope is shared with other HCOVs. Animal studies show this antibody to have neutralizing effects on Scov2 challenge but it does not seem to be elicited by everyone who gets infected. A vaccine that induces this particular broadly neutralizing HCOV antibody could be included in an HCOV intranasal vaccine.
https://www.science.org/doi/10.1126/scitranslmed.abi9215
II. Intranasal vaccines + intranasal antivirals = freedom
The other critical piece of the strategy to end the pandemic involves antiviral medicines. Tamiflu (oseltamivir phosphate) is a well-known antiviral drug that interferes with influenza's ability to replicate (multiply) inside the body. Tamiflu reduces the risk of developing pneumonia by 44%, and the risk of hospitalization by 63% when taken in the first 48 hours post-OOS.
By comparison, Paxlovid, an antiviral medicine that interferes with Scov2 replication, has been shown to lower the risk of developing severe C19 disease by about 90% and early studies show that, like Tamiflu, can be used prophylactically to prevent symptomatic infections.
1441. Both of these antiviral medicines are delivered orally. Tamiflu comes in both pill and liquid forms while the current version of Paxlovid comes as a pill. Pfizer, which makes Paxlovid, is working on a version of the drug that can be delivered intranasally as a spray. And a Canadian company, SaNOtize Research & Development Corp., along with India-based Glenmark Pharmaceuticals, has announced results from a Phase III trial of their Nitric Oxide Nasal Spray (NONS), showing a reduction in Scov2 viral load by more than 94% within 24 hours of treatment and by more than 99% in 48 hours. It was found to be safe and effective and shortened the course of the disease. NONS is believed to be able to prevent the transmission of the virus. It has been approved by India's public health regulatory body for high-risk adults with C19.
Making therapies like intranasal Paxlovid and NONS universally accessible at a low cost would enable people to treat infections early which might lower the risk of long-covid and organ tissue injury, abort infections immediately after known exposures, or prevent infections in situations where exposures are highly likely to occur such as when someone in the home is diagnosed with C19.
If you can imagine everyone having access to an effective anti-C19 nasal spray that can be kept in the medicine cabinet or carried in a purse, backpack, or pocket, you can imagine the end of the pandemic as we know it. If the person behind you on the plane, beside you in the theater, or sitting on your exam table is coughing or sneezing, you could spray it into your nose right away to prevent/abort an infection. Healthcare professionals could take it at the end of a day of seeing patients with suspicious respiratory diseases. An intranasal HCOV vaccine in combination with intranasal antivirals offers a way out of the pandemic.
Long-covid (LC) and delayed onset illness update
1442. Half of employers surveyed in the UK have employees with long-covid (LC) and a new study estimates that LC is driving employment shortages and a drop in productivity among the workforce. Official data show the number of people out of work due to long-term ill health has increased by 230,000 from pre-pandemic levels. Office for National Statistics figures show 1.3M people were reporting persistent symptoms of C19 at the start of 2022, and that almost a quarter of a million of them said their ability to undertake day-to-day activities was “limited a lot.”
https://www.ft.com/content/33444f29-bab1-4655-85b5-c0b1f68d9653
1443. A systematic review and meta-analysis of 81 LC studies published up to last June shows that 32% of people infected go on to have chronic fatigue and 22% reported cognitive impairment > 12 weeks post-infection.
https://www.sciencedirect.com/science/article/pii/S0889159121006516?via%3Dihub
1444. A new study from the UK among 11 to 17 YOs shows those who had positive C19 PCR tests are more likely to have symptoms of LC than those with a negative test result and were almost twice as likely to report three or more symptoms suggesting that, in the UK alone, tens of thousands of children and teens likely have LC. This is in line with an estimate from the UK Office for National Statistics that 44,000 2 to 11 YOs in the country have LC, as do 73,000 12 to 16 YOs. "Past disease outbreaks often led to lasting symptoms, such as post-polio syndrome, and COVID-19 is clearly no different."
https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00022-0/fulltext
1445. The effects on the testes of C19 patients by biopsy of post-mortem specimens taken 3 hrs after death, include: fibrosis, vascular alteration, inflammation, tunica propria thickening, Sertoli cell barrier loss, germ cell apoptosis, and inhibition of Leydig cells. There was Scov2 tropism of the testes in all cadavers. The virus preferred infection and replication in spermatogonia and remains infectious even after a long infection period, suggesting that the testes might serve as a viral reservoir. The longer the infection went on, the lower the number of residual surviving germ cells. Overall, intratesticular testosterone levels are 30x lower in testes of C19 patients compared to controls. Taken together, these findings bode poorly for the testicular health and long-term reproductive capability of men who contract C19.
https://www.medrxiv.org/content/10.1101/2022.02.05.22270327v1.full.pdf
1446. In a study comparing 153K people diagnosed with C19 against > 5M contemporary controls and 5M historical controls, C19 patients exhibited increased risks and an increased 12-month burden of CVA, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease and other cardiac disorders independent of age, race, sex, obesity, hypertension, diabetes, chronic kidney disease, hyperlipidemia, and other risk factors, including among those without any PMH of cardiovascular disease prior to C19. Critically:
The CVD risks and burdens were evident among those who had only mild acute disease.
The CVD risks and burdens exhibited a graded increase across the severity spectrum of the acute phase of COVID-19 (from non-hospitalized to hospitalized to those admitted to ICU).
Careful analysis shows that the increased CVD risks and burdens are attributable to C19. "Taken together, our results show that 1-year risks and burdens of cardiovascular diseases among those who survive the acute phase of COVID-19 are substantial and span several cardiovascular disorders.. The findings emphasize the need for continued optimization of strategies for primary prevention of SARS-CoV-2 infections..."
https://www.nature.com/articles/s41591-022-01689-3
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1447 - 1448. Tomorrow, Feb 15, 2022, California will lift its indoor masking mandate. Although medical spaces and other high-risk congregate environments like skilled nursing facilities (SNFs) will continue to have masking mandate protection, what will happen with schools is less clear and looks to be adjudicated at the local level with each district setting its own policy.
Throughout the pandemic, data have shown that the societies that pull together as one (like Japan), regardless of their anti-covid strategy, fare better than those that enact divided strategies (like the US).
Meanwhile, San Diego continues to have more than 2K reported cases per day which represents both a progressively diminishing number of cases from the peak a couple of weeks ago but also a progressively diminishing percentage of the actual number of cases as only positive PCR tests are included in the SDCDPH data and ever fewer people are seeking PCR tests, as we know.
This means that at the current moment, we are still having higher community prevalence than at any time since the start of the pandemic, pre-Omicron. What's more, the lifting of the masking mandate applies only to vaccinated people but it is unclear if that means 2 shots or 3–an issue that would be important if it were not moot since there will be no requirement to show proof of vaccination status and the rule will be enforced by the honor system in a culture where dishonesty has become normalized.
Does Governor Newsom misunderstand the term 'endemic' (see January 31, 2021 briefing) and so is leading us in the direction of a bad outcome by error or is he knowingly taking these actions in order to appease a highly vocal political minority demanding an end to an inconvenience which they have mistakenly come to believe, through misinformation and disinformation, is of no real benefit?
https://www.nytimes.com/2022/02/07/us/california-indoor-mask-mandate.html
1449. No surprise: vax'd college students spread covid much less than unvax'd.
1450. Seattle Children’s: During the Omicron surge, the incidence of croup nearly doubled compared to the rate in prior months with a sharp rise in cases of croup seen in pediatric ED in parallel with the replacement of the Delta VOC by Omicron.
https://www.medrxiv.org/content/10.1101/2022.02.02.22270222v1
1451. A new smartphone app can detect Scov2 infections with as much sensitivity/accuracy as PCR testing. Using LAMP to test for viral RNA, the test amplifies samples from saliva and costs just $7. It can also be used to detect influenza. The catch: right now it only works on Samsung Galaxy phones which have the right cameras to detect a positive test. What's needed? An LED light, a Samsung phone, and a hotplate. My note: promising study but small and the technology needs to be usable with other smartphone platforms.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788464?resultClick=3