Today, the FDA approved both Moderna and Pfizer vaccines for young children ages 6 months to 5 years. The vaccines generate a similar immune reaction in the little kids as they do in teenagers and while they may not be as good at preventing Omicron infections, they protect against severe disease. During the Omicron BA.1 wave, young children and babies were hospitalized more than any other time during the pandemic so vaccination is very important. In other news about children, the jury is still out on what exactly causes Pediatric Hepatitis of Unknown Origin, but a new report from Israel showed two types of pediatric hepatitis that were both related to prior COVID infection. The first type was found in babies and caused liver necrosis and the need for liver transplants. The second type was noted in older children and caused hepatitis with cholestasis that responded to steroids.
BA.4/5 are causing new waves across Europe and BA.4/5 cases are just starting to rise here in the U.S. Last week, BA.4 and BA.5 were 13% of U.S. cases and this week they are 21.6% of cases. Remember that BA.4 and BA.5 have mutations that make them more immune evasive meaning and they are not neutralized by antibodies from BA.1 infection or from vaccination as well. Because of this, there is a concern that BA.1 specific boosters may not be as effective against BA.4/5. We will have to see.
Although Omicron is perceived as being more mild than the Delta variant, in the UK, just as many people died of the Omicron variant (BA.1, BA.2) in the first 5 months of 2022 as did during the 6 months of the Delta variant wave. BA.4/5 is thought to affect the lungs more than BA.1 did. We are finding that different countries (South Africa vs Portugal for example) have had different BA.4/5 case curves that probably depend on prior infections and how long ago people received their last vaccination.
There are several excellent reviews and threads discussing Long COVID (PASC) this week. The UK reports that so far there is less Long COVID with Omicron- 4.5% Long COVID with Omicron versus 10.8% of Long COVID from Delta infections. In Science magazine this week, 3 theories of Long COVID causes are explored at length- 1) microclots, 2) persistent virus and 3) prolonged immune system activation. The article didn't mention autoimmunity. Another article and Twitter thread from Dr. Monje's lab at Stanford shows why a mild COVID infection in the lungs can signal an inflammatory reaction in the brain. The neuroinflammation can consequently cause neural cell dysregulation that can affect brain function and induce "brain fog" in Long COVID patients.
A new small study from Harvard today shows that 60% of Long COVID or PASC patients that they studied had persistent SARS-CoV-2 spike antigen in their plasma up to 12 months after their original COVID infection. This strongly suggests that a viral reservoir somewhere in the body (in the gut for example) may continue to shed spike antigen into the blood of Long COVID patients. Dr. Akiko Iwasaki also posted a very good Twitter thread this week on how persistent viral RNA may be causing Long COVID and that targeting viral reservoirs may treat Long COVID.
Finally, I highly suggest that you read Dr. Bob Wachter's Twitter thread on why he chooses to wear a mask indoors until the number of cases in his area is less than 10-20 cases/100,000 people per day. His reasons include: "1) Tens of millions of people with Covid will have ongoing symptoms that interfere with quality of life; in some they’ll be disabling, & 2) A Covid infection may significantly increase the long-term risk of non-infectious problems like heart attacks, diabetes, & dementia. I’m totally aware of what a bummer this is, & how nice it would be to wish Long Covid away. But I can't."
World: BA.4 and BA.5 are causing new waves in Europe and South Africa and are causing an increase in hospitalizations
NY Times: US cases 6/15/22
>100,000 new cases per day in the U.S., a figure that has stayed roughly flat for the month of June.
Cases are declining in roughly half the states, particularly in the Northeast and Midwest.
In the South and West, cases and hospitalizations are increasing substantially. Wyoming and Mississippi have significant increases in cases and hospitalizations.
Medriva: US Test Positivity 7 day average is 26.2%
Walgreens test positivity is similar at 28.8% positivity for this week:
NY Times: US cases
BA.4/5 is 21.6% of cases this week in the US. (Up from 13% last week).
CDC Wastewater
6/17/22 The FDA authorizes Moderna and Pfizer COVID vaccines for the youngest childrenhttps://buff.ly/3Hx05Wc
Moderna’s two-dose vaccine is for children 6 months through 5 years old, while Pfizer’s three-dose vaccine is for children 6 months through 4 years old.
2 doses of Pfizer prevented 28% of infection, 3 doses of Pfizer prevented 80% of infections.
Moderna’s vaccine was about 51% effective in preventing infection in children 6 months to 2 years old and 37% effective in children 2 through 5.
Both vaccines provoked an immune response comparable to that triggered in young adults and both prevented serious illness.
Moderna’s vaccine might trigger an immune response “slightly more rapidly,” while Pfizer’s might “bring a greater response after the third dose.”
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.
In PASC patients’ plasma:
60% had spike protein
20% had S1
1 patient had N detected
Sampling longitudinally is important.
6/17/22 Nature: BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron (BA.1) infection https://buff.ly/3tHAtR1
BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron (BA.1) infection.
Monoclonal antibodies Bebtelovimab and Cilgavimab can effectively neutralize BA.2.12.1 and BA.4/BA.5.
Because BA.2.12.1 and BA.4/BA.5 are very immune evasive and escape antibodies made during BA.1 infections, there are concerns that BA.1 specific vaccine boosters may not be as effective.
6/16/22 Science: What causes Long Covid? Here are the three leading theories https://buff.ly/3Hy9qx3
3 theories that combined may be causing Long COVID (PASC):
Microclots
Persistent virus
Immune system activation (immune system gone haywire)
The US CDC recently said that 1 in 5 people with COVID now have Long COVID.
Lung SPECT-CT scans identify microclots indirectly, based on blood flow abnormalities.
6/16/22 Lancet: Risk of Long COVID associated with Delta versus Omicron variants of SARS-CoV-2 in the UK https://buff.ly/3QsUl3N
Symptomatic and asymptomatic infections
Long COVID (PASC) seen in:
4.5% of Omicron cases
10.8% of Delta cases
Overall, we found a substantial reduction of Long COVID with the Omicron variant versus the Delta variant with an odds ratio of 0.24 –0.50 depending on age and time since vaccination.
6/16/22 Science (via John Chi): Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure https://buff.ly/3xqknMA
Prior infections with the ancestral (Wuhan) virus or the Alpha variant caused imprinting (“antigenic sin”) which reduced immune response (decreased immune recognition at the B cell, T cell, antibody binding and nAb level) to Omicron infection.
That previous SARS-CoV-2 infection history can imprint such a profound, negative impact on subsequent protective immunity against Omicron is an unexpected consequence of COVID-19.
6/16/22 NEJM (Qatar): Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections https://buff.ly/3HxrveF
VE against symptomatic BA.2:
46% VE for previous infection alone
52% VE for 3 doses of Pfizer vaccine and no previous infection
55% VE for previous infection and 2 doses of Pfizer vaccine
77% VE for previous infection and 3 doses of Pfizer (hybrid immunity)
VE against severe or fatal BA.2 infection was >70% for previous infection alone, Pfizer vaccination alone, and hybrid immunity.
6/16/22 Reuters: Pfizer stops enrollment in Paxlovid trial in standard-risk populationhttps://buff.ly/3QuGWbQ
Paxlovid is approved (EUA) to reduce hospitalizations and deaths in high-risk groups including people over age 65.
In this study, Paxlovid showed a 51% relative risk reduction in standard-risk groups, which the company said was not statistically significant.
6/16/22 NY Times: 49 states preordered vaccine doses for very young children from the federal government. Florida did not. https://buff.ly/3xxoxSQ
6/17/22 After Public Pressure, Florida Allows Pediatricians to Order Vaccines for Very Young Children https://buff.ly/3y14s93
6/15/22 Dr. Fauci tests positive for COVID-19.
6/15/22 FDA advisers just voted unanimously (21-0-0) to recommend emergency use authorization for the Moderna vaccine for infants and children 6 months through 5 years old.
6/15/22 FDA advisers back Moderna's COVID-19 vaccine for older kids and teens https://buff.ly/3QBl7r9
The FDA will now vote whether to approve Moderna vaccine for children ages 6 to 17.
Moderna vaccine effectiveness was estimated at 93% for the teens, and 77% for the younger children pre-Omicron.
The committee will also be evaluating the Moderna vaccine data for kids under age 6.
Becerra tested negative for COVID before returning to the United States and multiple times afterward. He then tested positive on Monday.
His new COVID infection happened less than a month after his last.
6/14/22 Cell: Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation https://t.co/vuq39XlB2z
"Chemo brain" and Long COVID "brain fog" have similar neuropathology including elevated CCL11 levels with impairment in hippocampal neurogenesis, microglial reactivity, and loss of myelinating oligodendrocytes after mild respiratory COVID.
Immune responses to infections outside of the brain can cause neuroinflammation and consequently neural cell dysregulation that can affect brain function.
As for treatment for Long Covid, there are lots of anecdotes (including [below], from my colleagues @UCSF, that a course of Paxlovid given to people with LC might work) but we still need a lot more data to be sure.
5/9/22 UCSF: COVID Drug Paxlovid May Also Ease Symptoms of Long COVIDhttps://buff.ly/3PmHGiH
6/13/22 PNAS: Quantifying the importance and location of SARS-CoV-2 transmission events in large metropolitan areas https://buff.ly/3O6Ceim
Compared New York City and Seattle data during the first COVID-19 wave.
Transmission risk is a combination of both the characteristics of the place/setting and the behavior of individuals who visit it.
18% of individuals produce most infections (80%), with about 10% of events that can be considered superspreading events (SSEs).
Although mass gatherings present an important risk for SSEs, the bulk of transmission occurred in smaller events in settings like workplaces, grocery stores, or food venues.
6/1/22 PLOS Review by Diane E. Griffin: Why does viral RNA sometimes persist after recovery from acute infections?https://buff.ly/3xI6tXs
Persistence of viral RNA following RNA virus infection can be associated with late progressive disease or nonspecific lingering symptoms of post-acute infection syndromes (#PAIS).
Consequences of persistent viral RNA may include organ-specific as well as nonspecific postviral syndromes such as long COVID, post-Ebola, and post-polio syndromes, characterized by symptoms including fatigue, headache, muscle pain, and joint pain.
WHERE viral RNA can persist?
After a variety of RNA virus infection, viral RNA can persist not only in immune privileged sites (brain, eyes, and testes), but also in blood, lymphoid tissue, joints, respiratory tract, GI tissues, and kidney.
WHAT is the nature of persistent viral RNA?
Naked viral RNA would be quickly degraded by host RNases. Persistent RNA may be in the form of:
1) Persistent infectious virus
2) Full-length viral RNA
3) Degraded viral RNA
Evidence for 1) and 2) are discussed.
Ribonucleocapsid or membranous structures may protect the viral RNA.
Long lived cells like neurons with viral RNA persistence reflects the ability of infected cells to avoid elimination by immune mechanisms - innate immunity, antibodies and T cells.
Short-lived cells like epithelial cells commonly permit rapid cell-to-cell transfer of viral nucleocapsids
Direct cell-to-cell transmission of respiratory viruses: The fast lanes https://buff.ly/3HeRwPH
Persistent viral RNA can drive chronic innate immune stimulation.
Proteins from viral RNA translation can also drive chronic adaptive immune stimulation that can lead to prolonged inflammation.
“Identification of the role of RNA persistence in late disease could be advanced with longitudinal studies that evaluate treatments that suppress RNA replication and examine their effects on RNA persistence and long-term outcomes.”
Persistent viral RNA has been seen post-COVID and after other viral infections.
Targeting and getting rid of persistent viral RNA may hold the key to the treatment of Long COVID and ME CFS.
Joint ECDC-WHO Regional Office for Europe Weekly Hepatitis of Unknown Origin in Children Surveillance Bulletin https://buff.ly/3xORfzO
Worldwide: WHO notes 700 cases globally and 10 deaths.
Europe:
402 cases in 20 countries. (102 new cases reported in last 2 weeks)
36% of children needed ICU care & 9% got liver transplants.
78% of the children are under the age of 5.
54% tested positive for Adenovirus.
10.6% tested positive for active SARS-2 infection.
Only 47 cases were tested for prior SARS-2 infection and 64% of these were positive.
Of the 94 cases with data on COVID-19 vaccination, 85% were unvaccinated.
6/12/22 Journal of Pediatric Gastroenterology and Nutrition: Long COVID-19 Liver Manifestation in Childrenhttps://buff.ly/3HfSwDa
a.k.a. Pediatric Hepatitis of Unknown Origin
Five pediatric patients who recovered from COVID-19 and later presented (21 to 130 days, avg. 74 days later) with liver injury. No adenovirus found.
Two types of Liver damage:
1. Acute liver failure that rapidly progressed to liver transplantation in two previously healthy infants aged 3 and 5 months.
Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate.
2. Hepatitis with cholestasis in three children, two aged 8 years and one aged 13 years,
Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations.
All three were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment.
The mechanism of liver manifestation is either a post-infectious immune reaction similar to MIS-C, or an immune dysregulation causing priming to other infectious agent such as adenovirus by a prior infection with SARS-CoV-2
