As of last Tuesday, BA.5 represents 65% of new cases in the United States. BA.5 is causing elevated infection rates leading to increasing hospitalizations around the world. Hospitalizations in the US have now risen above 40,000 per day and 55% of the US population now lives in a county classified as being "high risk" based on hospitalizations. It is time to mask again indoors. Los Angeles county, home to 10 million people and the largest county in the United States, has surpassed their hospitalization cut off and so masks will soon be mandatory indoors in L.A. Official US test positivity was reported as 17% which is quite high, but Walgreens pharmacy, which tests people for free whether or not they have health insurance, is now showing a US positivity rate of 41.6%! That is unbelievably high.
BA.4 and BA.5 are known to have immune escape to our neutralizing antibodies which are part of our adaptive immune system. A new article this week shows that BA.4 and BA.5 can also evade our innate immune system by reducing epithelial cells' innate immune responses and by increasing innate immune antagonistic proteins thus affecting our first line of defense against pathogens.Innate immune system evasion was not previously seen with BA.1 or BA.2 variants. I review the innate immune system versus the adaptive immune system below.
So, BA.5 can evade both our innate immune system (epithelial cells, etc) and our adaptive immune system (evading antibodies made by our B cells), but this week another study shows that BA.5 is also more transmissible because it can use the TMPRSS2 protein more efficiently to enter our cells. The combined immune evasion and increased transmissibility of BA.5 are leading to the high number of infections and to rising hospitalizations. There are some reports that it takes a longer time to become negative on a rapid antigen test with a BA.5 infection than with previous variants. Therefore, the 5 days of isolation plus 5 days of masking as recommended by the CDC are also probably not long enough.
The White House had a press briefing this week recommending that all adults over age 50 should get a booster now if they have not had one in 2022. Dr. Ashish Jha also recommended Evusheld for immunocompromised people and using Paxlovid or Bebtelovimab for those who qualify to avoid hospitalization. He also recommended using rapid antigen tests before indoor gatherings and/or masking indoors and improving ventilation inside as well.
According to the Washington Post, Biden officials are pushing to allow second boosters (i.e. 4th dose) for all adults age 18 and above. BA.5 is so much more infectious and reinfections are also more common, even if someone recently had a different COVID infection in the last 1 to 2 months. Immunity wanes over time after vaccination and hospitalizations are increasing. Allowing adults age 18 to 49 to get a second (dose 4) booster, will help to reduce overall infection numbers which will make it safer for us all. Plus, vaccine doses are plentiful now and in fact, many recently were thrown out when they expired. I expect that the CDC will recommend 2nd boosters (dose 4) for all adults some time next week.
People have been asking me if they should get their 2nd booster dose now, or wait until the fall when the bivalent vaccine may become available in the fall. My response is: Don't wait, get the booster now! The White House has said that they will allow people to get the bivalent vaccine in the fall even if they get a booster dose now. Getting a booster will increase a person's neutralizing antibody levels thus helping to protect against BA.5 better now. Unfortunately, despite many studies showing the benefit, especially in people over age 50, of getting the second (dose 4) booster in preventing severe disease and death, only 9% of Americans age 50 to 64 years old and only 22% of those age 65 and older have gotten their second (dose 4) booster so far.
Have a good weekend,
Ruth Ann Crystal MD
P.S. Scroll to the end of the articles for some fun animal stories.
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COVID news:
World
United States
US Covid hospitalizations crossed 40,000 for first time since the end of February and slope of their ascent is increasing. (h/t Eric Topol)
7/14/22 ABC7: LA County hits 'high' COVID activity level, starting countdown to return of indoor mask mandate https://buff.ly/3RD4gEM
Los Angeles county's rate of daily COVID-positive patients being admitted to hospitals topped 10 per 100,000 residents, thus entering the "high" category.
Masks will be required in all indoor spaces 2 weeks later on July 29 if this continues.
UK:
7/14/22 Reuters: U.S. FDA authorizes protein based Novavax COVID vaccine for adults https://buff.ly/3Pbjb7u
The vaccine, already approved in Europe, is based on a technology that has been used for decades to combat diseases including hepatitis B and influenza.
BA.2.75:
Right now, we don’t know yet what is happening with BA.2.75. We’ll have to wait and see how it works out. There is a chance that some countries with large BA.2 waves will have some protection. But, there is not enough data yet being reported about BA.2.75 so we will just have to see.
7/15/22 FT: Coronavirus sub-variant ‘Centaurus’ (BA.2.75) spreads across India and parts of Europehttps://buff.ly/3RzfNou
Cases not reported does not mean that there are no cases.
BA.2.75, which has been nicknamed Centaurus, appeared to have mutated in a way that could indicate “major immune escape”, said the WHO’s chief scientist Soumya Swaminathan, adding that it showed a “clear growth advantage” over other variants in India.
“The virus is still transmitting, very widely. In doing so it is mutating. Some variants are fitter than previous variants — intrinsically more transmissible and/or better able to evade immune responses,” he said. “Immunity lasts less time than we had hoped, so people can be infected repeatedly, with cumulative damage.” said Peter English, a retired consultant in public health.
The latest picture for the new BA.2.75 sub-lineage (nickname: "Centaurus") - a "2nd generation" evolutionary jump from BA.2 show little spread in other countries besides India, but it is still early and there are not a lot of data points yet.
Long COVID and HBOT:
7/12/22 Nature: Hyperbaric oxygen therapy (HBOT) improves neurocognitive functions and symptoms of post-COVID condition (PASC, Long COVID): randomized controlled trial https://buff.ly/3Psm8QE
Randomized, sham-control, double blind trial on HBOT. n = 36 in each group.
Significant improvement in:
Fatigue symptoms (d = 0.522, p = 0.029),
Sleep (d = − 0.48, p = 0.042),
Psychiatric symptoms (d = 0.636, p = 0.008), and
Pain (d = 0.737, p = 0.001).
Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate.
Hyperbaric Oxygen Therapy (HBOT) can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition.
HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.
7/12/22 YouTube: Press Briefing by White House COVID-19 Response Team https://buff.ly/3o3lyNy
7/12/22 CDC on COVID vaccine US Boosters given by age (via @CarlosdelRio7):
7/13/22 Washington Post: Booster shot confusion: get them now, or wait for better?https://buff.ly/3O7KkXI
For those under age 50, if you are unlikely to do mitigation measures like masking indoors, it would be best to get the booster now.
Expanded eligibility for boosters for those under age 50 will help protect first responders, essential workers and those who must mingle with large crowds.
Doses are available now and when the bivalent booster vaccine comes out later this year, people will still qualify to get it then.
7/14/22 Nature: One coronavirus infection wards off another — but only if it’s a similar varianthttps://buff.ly/3o9Aeuw
Summary of the Qatar study below:
Protection from prior infection wanes over time, but still protects against severe COVID.
The study, which analyses cases in the entire population of Qatar, suggests that future surges will not leave hospitals overcrowded with COVID patients.
7/12/22 MedRxiV (Qatar): Protection of SARS-CoV-2 natural infection against reinfection with the BA.4 or BA.5 Omicron subvariants https://buff.ly/3OhKKed
Protection of a previous infection against BA.4/BA.5 reinfection was modest when the previous infection involved a pre-Omicron variant, but strong (75-80% VE) when the previous infection involved the Omicron BA.1 or BA.2 subvariants.
But, protection of a previous infection against BA.4/BA.5 was lower than that against BA.1/BA.2 because of greater immune escape with BA.4/5.
BA.1 booster vaccine might help protect against BA.5.
7/12/22 BMJ: Effectiveness of a fourth dose of covid-19 mRNA vaccine against the Omicron variant among long term care residents in Ontario, Canada: test negative design study https://buff.ly/3nMQdPd
30 December 2021 to 27 April 2022
Compared with a third dose of mRNA covid-19 vaccine, a fourth dose improved protection against infection, symptomatic infection, and severe outcomes among long term care residents during an omicron dominant period.
A fourth vaccine dose was associated with strong protection against severe outcomes in vaccinated residents compared with unvaccinated residents, although the duration of protection remains unknown.
7/12/22 BioRxiV: Enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants BA.4 and BA.5 https://buff.ly/3APC63g
BA.4 and BA.5 evade the adaptive immune system with immune escape from antibodies.
BA.4 and BA.5 evade the innate immune system by reducing epithelial innate immune responses and increasing innate immune antagonist proteins Orf6 and N for increased immune evasion.
This was not previously seen in prior Omicron variants (BA.1, BA.2).
Non-specific immunity, rapid, early response in minutes to hours.
The body’s first natural line of defense.
This system does not differentiate from one pathogen to another.
Its primary goal is to prevent any intruder from gaining access to the underlying tissues.
Physical barriers: skin, mucous membranes stop or trap pathogens.
Chemical barriers: antimicrobial compounds in tears, acid in our stomachs.
Innate immune cells: Non-specific.
Innate immune cells simply discriminate between “self” and “non-self,” thereby providing a broad range of protection.
Mast cells are one type of white blood cell within innate immunity and are found in the skin and mucosa, where they search for foreign material.
When located, they release a signal to queue reinforcements (additional white blood cells) to the area.
Adaptive Immune System:
Targeted immunity against specific pathogens, delayed response in 1-3 days.
T cells:
Helper T-cells, the cells that receive signals from the dendritic cells or macrophages.
Effector T-cells, activate other WBCs, including B-cells and memory T-cells, which keep a record of this antigen for future reference.
Cytotoxic (or killer) T-cells kill already infected or dying cells.
B-cells: make antibodies against pathogens (a.k.a. the humoral immune response).
B-cells produce antibodies which “tag” pathogens for destruction by Macrophages, before the pathogen can enter a host cell.
B-cells also produce Memory B-cells when they encounter an antigen to remember and protect against the same pathogen in the future.
7/12/22 There is a great need now for nasal boosters and variant-proof pan-coronavirus vaccines.
We need to think beyond mRNA vaccines that chase each new variant as it takes 5 to 6 months to get those up and running and by the time they are available, a new variant is spreading.
Nasal spray boosters to boost IgA in the nose and throat to stop virus entry and
Variant-proof vaccines (pan-betacoronavirus or pansarbecovirus vaccines) that are based on broadly neutralizing antibodies or mosaic nanoparticle vaccines like the one from CalTech that can neutralize all variants.
7/12/22 Science: ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies https://buff.ly/3nX7dSP
7/11/22 Washington Post: Biden officials push to offer second booster shot to all adultshttps://buff.ly/3yBevR0
Virus levels have risen across the country, fueled by ever-more-contagious Omicron subvariants such as BA. 5 that evade some immune protections and have increased the risk of reinfections. Hospitalizations are also increasing.
Immunity wanes within several months of the first booster shot.
BA.5’s ability to infect cells is more akin to Delta than the previous Omicron variants.
BA.5 has far better ability to get into cells (tropism related to TMPRSS binding efficiency) and this may be related to anecdotal reports of it taking a very long time to test negative after BA.5 infections, often exceeding 10 days.
Significant immune escape of BA.5 to neutralizing antibodies and to Evusheld monoclonal antibodies than prior Omicron variants.
BA.5 is the worst variant we have seen so far, because of its severity of immune evasion and transmissibility compared with any prior SARS-CoV-2 variant. But, fortunately we are facing it with some immunity from vaccines and prior infections.
BA.5 hospitalizations are rising in the US and many European countries, and there are new case spikes now in Israel, Japan, Singapore, New Zealand, Australia, Indonesia, China, and Brazil. Many of these case surges are also accompanied by an increase in hospitalizations.
The good news is that ICU admissions and deaths are not going up nearly as much as the increase in hospitalizations.
Our best protection from BA.5 infections and reinfections now consists of high-quality, well-fitted masks, physical distancing, air filtration, ventilation and vaccination and boosters.
BA.5 is more immune evasion AND more transmissible:
7/11/22 MedRxiV (Australia): SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. https://buff.ly/3RqqYQs
It appears that BA.5 can evade neutralizing antibodies more and it also can more efficiently use TMPRSS2 to enter cells making it more transmissible.
BA.5 shows a drop in potency of Evusheld and Sotrovimab mAbs.
Several articles are being written now about this small study from Harvard on possible Long
COVID biomarkers.
6/17/22 MedRxiV (Harvard): Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae (PASC)https://buff.ly/3b5tdrA
In 63 Long COVID (PASC) patients of which 61 were not hospitalized,
SARS-CoV-2 spike antigen was found in 60% of PASC patients up to 12 months post-diagnosis, strongly suggesting a SARS-CoV-2 viral reservoir in the body.
Reinfections are more common with BA.5 and a lot of people who just had COVID in February, March, or April and now have it again.
“BA.5 is doing what Omicron does but with a marginally more effective immune evasion,” Kall told me. “I don’t believe that it represents a massive paradigm shift.”
Waves of sick employees even with "mild" infections are still disrupting sectors that were already reeling from the Great Resignation—including the health-care system.
An exodus of experienced colleagues and untenable levels of burnout have trapped health-care workers in a chronic state of crisis.
Despite infection in astroglial cells, there is minimal infection of other neural cell types, including neurons.
Surprisingly, astrocyte infection is unlikely to be mediated by ACE2 and instead glycoproteins CD147 and DPP4 expressed on astrocytes are necessary and sufficient for SARS-CoV-2 infection.
7/13/22 BMJ: Incidence, risk factors, natural history, and hypothesized mechanisms of Myocarditis and Pericarditis following covid-19 vaccination: living evidence syntheses and review https://buff.ly/3nXBJfz
Meta-analysis of 46 studies.
Use of a Pfizer vaccine over a Moderna vaccine and waiting for more than 30 days between doses might be preferred for teen and young adult men.
Clinical course of mRNA related myocarditis appeared to be benign.
7/11/22 PharmaLive: Long COVID evidence begins to mount, suggesting biomarkers and a “triangle” effect https://buff.ly/3o25s6R
via Peter Tam:
Harvard study showed in 37 participating patients with Long COVID, 65% had detectable levels of viral antigens in their plasma samples. The most common was the spike protein was detected in 60%.
Phase II studies being done or planned for Long COVID treatment:
Axcella Health's candidate AXA1125 for insulin resistance, inflammation and fibrosis.
Thromboprophylaxis with Johnson & Johnson’s Xarelto (rivaroxaban).
Trintellix (vortioxetine), a known antidepressant, is to be tested for post-COVID-19 cognitive problems. Study is enrolling.
Genentech’s Esbriet (pirfenidone) is being tested against pulmonary fibrosis after COVID-19.
Shots were unused due to vaccine hesitancy, improper storage and donations delivered close to expiration dates.
7/11/22 Tweet by David Steadson, epidemiologist who works at a digital health startup, on cumulative risks of repeat infection on Long COVID (LC).
Via Jonathan Schaffer
Curves may not reflect differences in:
Specific variant’s risk of LC
Immune status- vaccines, boosters
Comorbidities, age
Important to think about the cumulative effect of repeat COVID infections on Long COVID (and other long term health risks like cardiovascular disease, stroke, diabetes, etc.)
5/6/22 ONS link: Self-reported long COVID after infection with the Omicron variant in the UK - Office for National Statistics https://buff.ly/3yoFReO
In Europe, The number of new Covid admissions fuelled by BA.5 has grown by
40% in the last week in France
34% in England
>20% in several other European countries.
So far, deaths are lower than prior waves.
In the US, hospital admissions are at 6% which probably relates to the decline of the BA.2 wave.
However, hospitalizations are expected to go up with BA.5.
Because BA.5 is so immune evasive, it will infect many people and even if a small percent of that large number are hospitalized, that will be a large number too.
