Although Omicron COVID cases are coming down, they are still at about 550,000 per day in the U.S. and 83,000 new cases per day in California. The curve up for Omicron was very steep, but the cases are decreasing at a slower rate here.
We are still learning about BA.2, the sister Omicron variant. The BA.2 variant has a clear growth advantage over BA.1 (the original Omicron) in Europe and Asia (India, Singapore, Philippines, Denmark, Sweden). UKHSA data from today shows that BA.2 is about 30% more transmissible than BA.1. The good news is that in early studies, BA.2 does not appear to have more immune evasion which means that our vaccines should work similarly against BA.2. New UKHSA data confirms that vaccination plus booster (3 doses) protects 63% against BA.1 and 70% against BA.2 symptomatic breakthrough infection. Scientists believe that while BA.2 may create a substantially longer tail of circulation of Omicron than would have existed with just the original Omicron BA.1, it probably won't cause another wave.
This week, there are a lot of articles on Long COVID (a.k.a. post acute syndrome of COVID or PASC) this week including:
4 factors that increase long COVID include higher viral load, autoantibodies, reactivation of Epstein-Barr virus and possibly Type II diabetes.
There is an immunoglobulin signature that combined with other factors can predict who will get Long COVID.
Neurologic long COVID causing cognitive symptoms appears related to pre-existing risk factors and abnormal OCB patterns in the CSF.
The gut microbiome is different in long COVID and a reservoir of virus in the intestines can cause abdominal pain and GI long COVID symptoms.
2 doses of vaccine in the UK decreased the risk of Long COVID by 41% as compared to unvaccinated people.
So, we need to be patient as the Omicron numbers go down more slowly than they did initially in South Africa. But, the numbers are going down and things should start looking a lot better in February.
Have a good weekend,
Ruth Ann
COVID NEWS:
World
United States
United States (NY Times): Decoupling of infections from hospitalizations and deaths in some states and not in others because of vaccinations.
There is not yet enough data to assess severity of BA.2
In England, BA.2 has a clear growth advantage over Omicron (BA.1).
13.4% of BA.2 cases transmitted within their households vs 10.3% of Omicron.
This gives BA.2 a 30% increased transmission advantage over BA.1.
BA.2 is very unlikely to be anything like the Omicron (BA.1) wave because of the very high levels of population immunity following the recent Omicron wave and boosters in the UK.
Plus, 2 promising early studies that suggest BA.2 is *not* more immune evasive than Omicron.
Given that Omicron 21K (BA.1) viruses spread easily in populations with prior immunity and given that on 1/27/22 UKHSA reported similar vaccine efficiency (VE) for 21K (BA.1) and 21L (BA.2), I'd suspect that 21L (BA.2)'s advantage derives from intrinsic transmission rather than greater immune escape.
Given differences in NTD between Omicron 21K (BA.1) and 21L (BA.2), it may be possible to see some re-infections of individuals recovered from 21K (BA.1) by 21L (BA.2).
I would guess we'll see 21L (BA.2) create a substantially longer tail of circulation of Omicron than would have existed with just 21K (BA.1), but that it won't drive the scale of epidemics we've experienced with Omicron in January.
1/28/22 Science by Derek Lowe: Omicron, Its Mutations, and the Antibody Response https://buff.ly/3ua6K4f
1/28/22 CDC: Effectiveness of a Third Dose of Pfizer-BioNTech and Moderna Vaccines in Preventing COVID-19 Hospitalization Among Immunocompetent and Immunocompromised Adults https://buff.ly/3g992Z7
The VE increased from 2-shot 82% to 3-shot (booster) 97% in people without immunocompromised status.
1/27/22 JAMA Pediatrics: Incidence of New-Onset Type 1 Diabetes Among US Children During the COVID-19 Global Pandemic https://buff.ly/3u8f3xu
Type 1 diabetes (T1D) is a disorder of autoimmune-mediated pancreatic β-cell destruction and decreased insulin production.
Incidence of new onset Type 1 Diabetes increased 57% among San Diego children in the first year of the COVID pandemic.
2019: 119 children diagnosed with Type I Diabetes
2020: 187 children diagnosed with Type I Diabetes
COVID:
Only 4 of 187 patients (2.1%) had COVID-19 infection at the time of presentation.
Study limitations include the lack of COVID-19 antibody testing at the time of diagnosis to investigate possible past infection.
There was also a significant increase in frequency of diabetic ketoacidosis (DKA) at diagnosis requiring pediatric ICU care.
1/27/22 BioRxiV: Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses in mice https://buff.ly/3r6H9Hc
Parenteral (intramuscular or IM) vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa.
Novel vaccine strategy: Prime and Spike
The Prime (primary IM mRNA) vaccination is given first and then the Spike (unadjuvanted intranasal spike protein) mucosal booster.
Prime and Spike
induces robust T resident memory cells (TRM), B resident memory cells (BRM) and IgA in the respiratory mucosa,
boosts systemic immunity, and
completely protects mice with partial immunity from lethal SARS-CoV-2 infection.
Instead of using a recombinant protein for the Spike, we show that spike mRNA encapsulated in immune-silent nanoparticle called Poly(amine-co-ester)s (PACE-Spike) intranasally was also capable of inducing TRM, BRM and mucosal Abs in the nose and respiratory tract.
Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.
Vaccine effectiveness holds up very well against BA.2 compared with BA.1 with booster
The vaccine effectiveness (VE) vs Omicron symptomatic infection vs Omicron falls off 15+ weeks, as was seen with the Israeli data, here more so with Pfizer compared to Moderna.
But protection (VE) against Omicron hospitalization remains quite high (Moderna > 90% thru 9 weeks).
95% VE against death with Omicron in people age 50+ (59% VE without booster)
Summary data for VE against Omicron over time for each outcome strongly reinforces the booster (dose 3) impact and the high level of protection maintained against hospitalization out to 6 months.
1/27/22 Science: Indirect protection of children from SARS-CoV-2 infection through parental vaccinationhttps://buff.ly/3rVGckf
Single vaccinated parent was associated with a 26% decreased risk of Alpha and 21% decreased risk of Delta infection in children.
Having two vaccinated parents was associated with a 72% decreased risk of Alpha and 58% decreased risk of Delta infection in children.
1/27/22 Science: Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement https://buff.ly/32CNn8p
To understand the Omicron antigenic shift, and how Omicron’s mutations result in most monoclonal antibodies not being able to block it.
Cryo-electron microscopy and X-ray crystal structures of the Omicron spike protein and the receptor-binding domain (RBD) bound to the broadly neutralizing monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor.
1/27/22 NEJM: Lung Transplantation for Covid-19–Related Respiratory Failure in the United States https://buff.ly/33YkAfd
From August 2020 through September 2021, 7% of lung transplantations nationally were performed in patients with respiratory failure due to Covid-19.
Patient survival was 100% for the 30 patients who had COVID-19–associated ARDS and 83% for the 72 patients without COVID-19, 1/2020 to 9/2021.
1/27/22 KHN: CDC Tells Pharmacies to Give 4th Covid Shots to Immunocompromised Patients https://buff.ly/3rgrgOR
Immunocompromised people were being turned away by pharmacy employees unfamiliar with the latest CDC guidelines.
1/27/22 NEJM: SARS-CoV-2 Omicron Variant Neutralization after Moderna mRNA-1273 Booster Vaccination https://buff.ly/3s0h5Np
2 doses of Moderna had 35x lower neutralization titers against Omicron than those against the original virus.
After the Moderna booster (3 doses), neutralization titers against Omicron increased 20x. This may reduce risk of breakthrough infection.
Omicron neutralization substantially decreased 6 months after the booster.
1/27/22 Cell: COVID and the Lungs: Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVD-19 respiratory disease https://buff.ly/3s3AVrc
COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.
Post-COVID19 airways, but not blood, show T cells, B cells macrophages and proteomic changes.
Increased BAL cytotoxic T cells are linked to epithelial damage and airways disease.
BAL myeloid and B cell numbers correlate with the degree of lung CT abnormality.
1/27/22 NY Times: New Research from UW Hints at 4 Factors That May Increase Chances of Long Covidhttps://buff.ly/33PraEZ
1. Higher initial viral load (RNA)
2. Certain autoantibodies
3. Reactivation of Epstein-Barr virus (EBV)
4. Type II Diabetes possibly
Giving antiviral drugs soon after diagnosis might reduce viral load and help prevent long-term symptoms.
“The quicker one can eliminate the virus, the less likelihood of developing persistent virus or autoimmunity, which may drive long Covid,” Dr. Iwasaki said.
Reactivation of Epstein-Barr virus has been linked to conditions like chronic fatigue syndrome (ME/CFS), which some cases of long Covid resemble, and multiple sclerosis.
Patients with higher levels of autoantibodies had lower levels of protective antibodies against the coronavirus, possibly making them more vulnerable to reinfection.
The UW study in Cell:
Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae (PASC or Long COVID)https://buff.ly/3IDzhms
Longitudinal multi-omic studies associate PASC with autoantibodies, viremia and comorbidities.
Latent EBV reactivation and SARS-CoV-2 RNAemia at COVID-19 diagnosis anticipate PASC.
Subclinical autoantibodies negatively correlate with protective anti-SARS-CoV-2 antibodies.
Gastrointestinal PASC uniquely presents with post-acute expansion of cytotoxic CD8+ T cells specific to SARS-CoV-2 and to CMV.
1/27/22 Nature (Zurich): Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome (PACS) or Long COVIDhttps://buff.ly/3r2j0lb
Serum IgA and IgG for spike protein subunit 1 (S1) and of total Igs.
A immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, combined with age, history of asthma, and 5 symptoms during primary infection – is able to predict the risk of PACS independently of time point of blood sampling.
1/27/22 LA Times: Optimism as Omicron peaks in California, but new BA.2 subtype raises questions https://buff.ly/3G1BTJh
Good summary of data in California.
Overall Omicron surge has peaked in California, but progress across the state remains uneven.
California’s Omicron surge peaked in the week of Jan. 10-16, at 122,000 new cases per day. That figure has since dropped to 94,000 cases a day.
2 cases of BA.2 found in Santa Clara County. Experts are watching closely but are not overly concerned because of the immunity wall from vaccines and boosters.
Future: Dr. Anthony Fauci doesn’t expect that the pattern of huge challenging variants emerging twice a year will last forever.
“What likely happens when you have waves of this is that, after a while, there is enough background immunity — either from infection-plus-boost, or vaccine-plus-boost, or just plain infection-and-recover-from-infection — when you put it all together, you can have a degree of immunity in the community such that, even if new variants emerge, they don’t take that surge effect that we’ve seen with the … five surges that we’ve seen since early 2020,”
Booster shots confer significant vaccine effectiveness against visits to the emergency room.
1/27/22 Am Neuro Assn (UCSF): Risk factors and abnormal cerebrospinal fluid (CSF) associated with cognitive symptoms after mild COVID‐19https://buff.ly/3IFpoVu
n = 22 with cognitive PASC, n = 10 without after mild COVID
Adults reporting new, persistent cognitive symptoms (neuro Long COVID) after mild SARS-CoV-2 infection had:
Delayed symptom onset (1 to 6 months) in 43% of cases,
More pre-existing cognitive risk factors overall (Table 2- hypothyroidism, diabetes, HTN, anxiety, depression, learning disability, history of TBI, etc)
Higher proportion with CSF abnormalities (Abnormal oligoclonal banding (OCB) patterns were identified in 69%) compared to cognitive controls who also recovered from SARS-CoV-2 infection.
Mechanisms that may have a delayed onset include
microvascular injury,
persistent immune activation,
post-infectious autoimmune response.
Cognitive PASC participants had a greater number of pre-existing cognitive risk factors, suggesting some individuals may be selectively vulnerable, possibly in frontostriatal and/or frontoparietal brain networks.
#PASC #LongCOVID #brainfog
1/27/22 BMJ: Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome https://buff.ly/3o7vCWj
Observational evidence of alterations of gut microbiome in patients with Long COVID.
1/27/22 OB GYN Green Journal: In Vitro Fertilization and Early Pregnancy Outcomes After Coronavirus Disease 2019 (COVID-19) Vaccination https://buff.ly/3IIiwH4
COVID-19 mRNA vaccines were not associated with an adverse effect on ovarian stimulation or early pregnancy outcomes after IVF.
1/27/22 UK ONS: Self-reported long COVID after two doses of a coronavirus (COVID-19) vaccine in the UK https://buff.ly/3o3RUIu
2 doses of a vaccine before infection was associated with a 41% decrease in the odds of reporting Long Covid symptoms (as compared to unvaccinated).
1/27/22 Cell: Immune imprinting, breadth of variant recognition and germinal center response in SARS-CoV-2 infection vs. vaccinationhttps://buff.ly/3o5LHf3
Vaccination confers broader IgG binding of variant RBDs than SARS-CoV-2 infection.
In mRNA vaccinees, lymph nodes show abundant germinal centers.
Vaccine spike antigen and mRNA persist for weeks in lymph node germinal centers.
FT: The United States lags behind other high-income countries for boosters given
1/26/22 CDC MMWR: Omicron's impact on Emergency Room and Hospitalizationshttps://buff.ly/3AzmgYm
Although Omicron causes less severe disease overall (lower length of stay, ICU admission, and death), Omicron caused the highest reported numbers of COVID-19 cases and hospitalizations during the pandemic.
1/26/22 AP: China's Olympics COVID measures test residents' patience https://buff.ly/3FYEN1u
Olympic athletes are being isolated. Two have tested COVID positive so far.
Those who test positive are taken to a hospital if they have symptoms and to a quarantine hotel if they do not.
If anyone buys a cold or headache medicine in Beijing, they must do a COVID test.
Mass testing of neighborhoods and buildings around Beijing.
China’s government has stuck to a zero-COVID approach- and snuff out any outbreak, no matter how small, with lockdowns, mass testing and travel restrictions.
1/26/22 NY Times: Israeli panel recommends offering a fourth vaccine dose to people age 18 and over, but Israeli Health Ministry has not yet approved a fourth dose for all adults. https://buff.ly/33VzOBF
The 4th dose has provided:
3x to 5x protection against severe disease for people aged 60+.
5x increase in neutralizing antibodies in healthcare workers.
1/26/22 New CPR guidelines prioritize PPE in wake of contagious COVID-19 variants https://buff.ly/33VZTk7
The American Heart Association (AHA) has backpedaled and now says that all healthcare providers treating suspected or confirmed COVID-19 patients should wear a respirator (e.g., N95) along with other PPE (gown, gloves, and eye protection) when performing CPR.
FYI for StartX companies making home COVID tests:
1/26/22 MedCity News: Truepill creates a platform to help insurers now required to cover home Covid tests https://buff.ly/3rW1uOU
1/26/22 Tulio de Oliveira tweet thread: Increase in BA.2 is happening during an overall decrease in COVID cases in South Africa
1/26/22 AP: FDA halts use of antibody drugs that don't work vs. Omicron https://buff.ly/3G5aOFd
Regeneron and Eli Lilly monoclonal antibody cocktail drugs should no longer be used because they don’t work against the Omicron variant
Long COVID and autoantibodies:
Article from 12/2020 by Prof Akiko Iwasaki and colleagues:
1/25/22 MedRxiV: SARS-CoV-2 Omicron Transmission in Danish Householdshttps://buff.ly/3rJAuSA
11,937 households (2,225 with the Omicron VOC)
Household secondary attack rate (SAR) was 31% for Omicron and 21% for Delta.
Booster (3 doses vaccine)
Infections were reduced odds ratio (OR) 0.54
Transmission risk reduced OR: 0.72
Increased transmission for unvaccinated individuals, and a reduced transmission for booster-vaccinated individuals, compared to fully vaccinated individuals.
1/25/22 Science: Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants https://buff.ly/3nXaUIR
SARS-CoV-2 infection before or after vaccination gives a significantly larger boost to the neutralizing antibody response compared to two doses of vaccine alone.
Hybrid Immunity: Prior Covid infection and a vaccine dose
Breakthrough immunity: Breakthrough infection after 2 doses of vaccine
No data for 3 doses of vaccine in this study.
Boosters decrease death by 99%:
1/24/22 Bob Wachter MD of UCSF: Asymptomatic COVID positive patient rate is decreasing in San Francisco. This reflects decreasing amounts of COVID in the community.
The largest populous states. California, Florida and New York have decreasing new cases of COVID but Texas has not descended yet.
People with pre-existing conditions matter. The hashtag #IHaveAPreexistingCondition took off on Twitter 1/23/22.
1/24/22 JPGN: Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection https://buff.ly/3tWoqjr
Report of an 11 year old girl with chronic abdominal pain and elevated fecal calprotectin. Biopsy shows SARS-COV-2 virions in the colon and a dense lymphocytic infiltrate 3 months after acute infection, potentially linked to symptoms.
SARS-CoV-2 nucleocapsid antibody stain is brown in this small bowel biopsy
1/24/22 ABC: University of Michigan study shows mask mandates at schools show lower COVID transmission rates https://buff.ly/343ICoE
Virus spread was 62% higher in school districts without mask rules.
1/24/22 AstraZeneca press release 12/16/21: Evusheldlong-acting antibody combination retains neutralizing activity against Omicron variant in independent FDA study https://buff.ly/3427j4W
Evusheld is a combination of 2 monoclonal antibodies, tixagevimab and cilgavimab, that has an FDA EUA for pre-exposure prophylaxis (PrEP) of COVID-19. It is to be used in people who cannot mount an adequate antibody response to vaccines or infection or for those for whom vaccination is not recommended.
AstraZeneca is applying to use Evusheld to treat COVID-19 as well.
The TACKLE Phase III outpatient treatment trial of Evusheld showed it reduced the risk of developing severe COVID-19 or death (from any cause) by 50% compared to placebo in non-hospitalised patients with mild to moderate COVID-19 who had been symptomatic for seven days or less.
Evusheld is derived from B-cells donated by convalescent patients. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020.
The human monoclonal antibodies bind to distinct sites on the SARS-CoV-2 spike protein and were optimized by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding.
The half-life extension more than triples the durability of its action compared to conventional antibodies and could afford up to 12 months of protection from COVID-19 following a single administration.
Data from the Phase III PROVENT trial show protection lasting at least six months.
1/23/22 The City of San Francisco will pay people $1000 so that people without sick leave can quarantine for 10 days if they get COVID. https://buff.ly/32rzxFP
1/23/22 Cell: A Blood Atlas of COVID-19 defines hallmarks of disease severity and specificity https://buff.ly/3FNHrqD
Blood atlas delineating innate and adaptive immune dysregulation in COVID-19.
Shared and specific immune signatures of COVID-19, influenza and all cause sepsis.
Multi-omic immune profiling differentiates hospitalized patient severity in COVID-19.
Persistent immune activation involving AP-1/p38 MAPK was a specific feature of COVID-19.
1/23/22 BioRxiV Pfizer study: Neutralization of Omicron SARS-CoV-2 by 2 or 3 doses of BNT162b2 vaccine https://buff.ly/3nSsIVf
2 doses of Pfizer vaccine are not sufficient to neutralize Omicron well.
At 1 month and 4 months post dose 3 of Pfizer vaccine, neutralization of Omicron is preserved although the level of neutralizing antibodies does start to decline over time.
BA.2: Omicron sub-variant ‘under investigation’ in UK
Post-Christmas Covid case total in UK was nearly triple official figure, says ONS
Jacinda Ardern cancels wedding as New Zealand brings in Covid restrictions
Austria approves bill to make Covid jabs compulsory for all adults
2 articles on possible mechanisms of Omicron’s hyper-transmissibility:
1/23/22 Cell: Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission https://buff.ly/355SvTl
Spike S:655Y mutation, in the Gamma and Omicron VOCs, enhances viral replication and spike protein cleavage and increases viral transmission.
This may partly explain Omicron’s hyper-transmissibility, beyond its immune evasion.
1/23/22 BioRxiV: Omicron variant of SARS-CoV-2 exhibits an increased resilience to the antiviral type I interferon response https://buff.ly/3FTlGpl
Omicron has gained an elevated capability to suppress IFN induction upon infection and to better withstand the antiviral state imposed by exogenously added IFN-alpha.
Resilience to Type I interferon (our innate immunity) may partly explain Omicron’s hyper-transmissibility, beyond its immune evasion.
1/23/22 Nature: COVID vaccines safely protect pregnant people: the data are in https://buff.ly/3fRhU5n
The risks of COVID-19 during pregnancy — including maternal death, stillbirth and premature delivery — far outweigh the risks of being vaccinated.
Only around 40% of pregnant people in the United States have been vaccinated against COVID-19 by 1 January 2022.
The numbers are similarly low across the globe.
2 articles on how mRNA boosters reduce symptomatic Omicron by 50-66%:
1/23/22 MedRxiV: Effectiveness of BNT162b2 and mRNA-1273 COVID-19 boosters against SARS-CoV-2 Omicron (B.1.1.529) infection in Qatarhttps://buff.ly/32oBiUb
mRNA boosters reduce symptomatic Omicron infections by 50%.
1/23/22 JAMA: Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants https://buff.ly/3AqLacE
mRNA booster (3 dose vaccine series) reduced symptomatic Omicron infections by 66% when compared to 2 dose series.
1/22/22 CDC MMWR: COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence https://buff.ly/3FUk6ns
1/22/22 Washington Post, by Megan Ranney MD MPH: We’re used to stress in the ER. But Omicron has made our jobs impossible. https://buff.ly/3FTUQh9
“We can’t provide the right care at the right time anymore — and after two years, we’re exhausted from trying.”
