This week, I have some information to share about two other infectious diseases. First, polio has been found in certain counties in New York state in the wastewater and is consistent with spread. New York is recommending that children get booster vaccines for polio. Second, monkeypox (MPX) was declared a public health emergency in the United States about a week ago thus allowing the government to put funding into fighting monkeypox. A smallpox vaccine can be used to prevent MPX, but there are not enough doses for those at risk, so the US will try giving intradermal doses at one-fifth the dose to try to give the vaccine to more people. MPX is still mostly seen in men who have sex with men (MSM) and cases are rising exponentially in the US. In Europe, some countries are starting to see a decrease in cases with public health measures.
Two days ago, the CDC updated their recommendations for COVID quarantine and isolation. The focus is now for individuals to make their own decisions on their risk level and how they want to mitigate that risk. But, COVID is a contagious disease that affects more than one person at a time. Many doctors and public health figures disagree with the most recent CDC guidelines. According to the new CDC guidelines, people who are exposed to COVID no longer need to quarantine and people who are asymptomatic no longer need to be tested. The CDC says that they are relaxing guidelines because of high population immunity. But, the United States ranks 80th in the world for 2nd dose boosters for those over age 50 despite many studies showing that this second booster can really decrease risks of COVID. Only 10% of those age 50 to 64 and only 25% of those over age 65 have received their second boosters in the United States. Seven million people in the US are immunocompromised and are more likely to be affected by the new guidelines.
School will be starting again soon. A recent study of school districts in Massachusetts shows that when students and teachers mask, COVID cases and subsequent missed days of school are significantly decreased. Another study at Boston University showed that college students who were vaccinated and wore masks in class had a very low risk of classroom transmission of COVID. Wearing masks in schools can really help prevent SARS-CoV-2 spread. Improving air filtration can also help.
BA.5 cases have plateaued but are still at about 105,000 new daily cases in the US and test positivity is still high at 18%. Wastewater levels of SARS-CoV-2 virus locally in the Bay Area are starting to decrease, so cases should start to go down here soon. In European countries like France and Germany, BA.5 wave cases have peaked and are starting to decrease. There is a new variant in the US to keep an eye on called BA.4.6. The proportion of BA.4.6 has been slowly rising in the last 3 weeks and this week it makes up 4.8% of US cases. In contrast, BA.5 now represents 87% of cases in the United States. The new bivalent vaccine that will contain mRNA to the original virus and to BA.4/BA.5 will not be available until at least October. Europe says that they will require clinical trials of the new bivalent vaccine to be completed before giving it to people, but the US FDA says it will approve it before final clinical trial data is available probably because it is similar to the previous mRNA vaccines.
Bebtelovimab is the only monoclonal antibody that works against BA.5 and BA.4.6, but the federal government's supply will soon run out. Eli Lilly has said that it will start to sell Bebtelovimab commercially to states and hospitals for $2100 per dose. Evusheld, the pre-exposure prophylactic monoclonal antibody cocktail used by immunosuppressed patients, will not work against BA.4.6.
Long COVID:
There is a very well written article and Twitter thread by Dr. Akiko Iwasaki showing that Long COVID patients have low cortisol levels, often at half the normal level, despite having normal ACTH levels. This shows a dysfunction of the hypothalamic-pituitary axis in Long COVID patients. Because of this, treating Long COVID patients will not be as easy as just giving steroids. The article shows that most Long COVID patients do not have autoantibodies, but they do have some dysfunction in T cells, some B cells and some monocytes as well. In addition, some Long COVID patients have reactivation of Epstein-Barr Virus (EBV, mononucleosis) and Varicella (chickenpox).
In addition to Long COVID patients having low cortisol levels, they also are found to have SARS-CoV-2 spike protein and/or fragments of viral RNA in their blood signaling a reservoir of virus that is hanging out somewhere in their bodies. A new study in the Netherlands shows that 1 in 8 (12.7%) people with a COVID infection, followed prospectively, went on to develop Long COVID. Regarding possible treatments for Long COVID, there are currently 26 randomized clinical trials testing possible treatments, but many are small studies or they lack a good control group.
President Biden, like Dr. Fauci, recently had a rebound COVID infection after taking a course of Paxlovid. These high profile cases may discourage doctors and patients from using Paxlovid despite it being shown to help prevent severe COVID in those at risk. The dosing regimen of taking Paxlovid twice daily for 5 days was studied when Delta was the prevailing variant. At that time, only 1-2% of people on Paxlovid had rebound, and a similar number of control patients also had viral rebound. But, Omicron is a different beast. We need new studies to figure out what the best Paxlovid dosing regime is for Omicron infections- it may be that a longer course of 7 or 10 days of Paxlovid will be needed for Omicron.
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8/9/22
Polio in NY state:
Monkeypox (MPX):
8/10/22 AP: US will stretch monkeypox vaccine supply with smaller doses https://buff.ly/3Aeotdr
Dose-sparing approach administers just one-fifth the usual dose of the Jynneos vaccine just under the skin (intradermal) instead of deeper tissues (intramuscular doses).
Data about smallpox vaccine’s 85% effectiveness against MPX is from 1988 but the virus has mutated since then. We need real world studies from the current outbreak.
8/11/22 CDC: Summary of Guidance for Minimizing the Impact of COVID-19 on Individual Persons, Communities, and Health Care Systems — United States, August 2022 https://buff.ly/3Qlaat9
8/12/22 Lancet: Safety of COVID-19 vaccines in Pregnancy: a Canadian National Vaccine Safety (CANVAS) network cohort study https://buff.ly/3QoxTZt
COVID-19 mRNA vaccines are safe and effective when given during pregnancy.
COVID-19 vaccination among pregnant people continues to be lower than among non-pregnant females of reproductive age.
Given the risks of severe illness and adverse pregnancy outcomes from COVID-19, continuing to collect and disseminate data on the safety and effectiveness of COVID-19 vaccination in pregnancy and encouraging health-care providers to promote vaccination during all trimesters of pregnancy is imperative.
8/11/22 MedRxiV (@EpiEllie): Impact of Lifting School Masking Requirements on Incidence of COVID-19 among Staff and Students in Greater-Boston Area School Districts https://buff.ly/3vXH2zT
Removing mask protections at Massachusetts schools lead to significantly increased COVID19 cases, more student and staff absences, and disrupted learning.
School districts which removed mask policies:
Students had 40 more cases per 1,000 than schools that kept masking.
If all students who tested positive followed state guidelines to isolate for 5+ days, that's almost 20,000 extra missed school days.
Staff, including teachers, had 82 extra cases per 1,000 compared to school districts that kept mask requirements in place.
8/11/22 Lancet preprint: Persistent Circulation of Soluble/EV-Linked Spike Protein and Viral RNA in Individuals with Post-Acute Sequelae of COVID-19 (PASC) https://buff.ly/3bQkSc4
Spike protein and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC (a.k.a. Long COVID), regardless of their presence or absence during the acute COVID-19 phase.
8/10/22 MedRxiV: Distinguishing features of Long COVID identified through immune profiling https://buff.ly/3zKYAAp
Symptoms:
Long COVID participants reported a number of symptoms, most commonly fatigue, brain fog, dysautonomia..etc. Hierarchical clustering of binary symptom data identified 3 clusters of patients with similar sets of self-reported symptoms.
Peripheral blood mononuclear cells:
LC had increase in non-conventional monocytes, activated B cells double-negative B cells, and decrease in conventional dendritic cells 1.
T cells:
Long COVID participants also had reduced central memory T cells and increased exhausted CD4 and CD8 T cells. The exhausted T cells suggest chronic antigens stimulating these T cells.
Long COVID patients also had increases in CD4 T cells that secrete IL-2, IL-4 and IL-6, as well as some that secrete both IL-4 and IL-6. These T cells correlated with the levels of EBV reactive antibodies.
Low Cortisol in LC, but normal ACTH:
Cortisol levels in LC patients were about half of the control groups. Despite this, we saw no elevation in ACTH levels, suggesting an impaired compensatory response by the hypothalamic-pituitary axis.
Autoantibodies (AABs)? No.
In contrast to what we found for acute severe COVID, long COVID group did not have elevated AABs.
Long COVID patients with tinnitus and nausea had elevated levels of sodium ion transporter AABs.
Reactivation of EBV and VZV:
Elevation in IgG against herpesvirus antigens in LC patients. In particular, antibody reactivity to glycoproteins and early antigens of Epstein-Barr virus, Varicella zoster virus were elevated in long COVID over other groups.
Low Cortisol and other biomarkers for Long COVID:
Serum cortisol was the most significant individual predictor of Long COVID status.
Several features significantly distinguished Long COVID (double negative B cells, serum galectin-1, various EBV epitopes) while others were negatively associated (serum cortisol, PD-1+ CD4+ TCM, and HSV1 and HSV2 motifs).
Long COVID group had much lower plasma CORTISOL levels, but normal ACTH.
Data suggests recent reactivation of EBV and VZV in Long COVID.
8/10/22 Nature: Long-COVID treatments: why the world is still waiting https://buff.ly/3Ab6Yuy
Although at least 26 randomized clinical trials of long-COVID therapies are under way, many are too small or lack the necessary control groups to give clear results.
“If you look at long COVID at this moment in time, I’d paint a slightly ‘Wild West’ and desperate picture really,” says immunologist Danny Altmann at Imperial College London.
4/23/22 How to safely let athletes go back to sports after a COVID infection
BMJ: Graduated Return to Play (GRTP) after SARS-CoV-2 infection – what have we learned and why we’ve updated the guidance https://buff.ly/3vVBl5y
8/11/22 PNAS: Morphological, cellular, and molecular basis of brain infection in COVID-19 patients https://buff.ly/3QB0MkL
Astrocyte infection with can lead to neuronal death or dysfunction by alteration of metabolites used to fuel neurons.
The COVID-19 group presented higher levels of anxiety and depression symptoms, fatigue, and excessive daytime sleepiness.
Patients with mild COVID showed cortical atrophy in the brain and cognitive dysfunction as compared to matched controls.
8/10/22 BioRxiV: Further humoral immunity evasion of emerging SARS-CoV-2 BA.4 and BA.5 subvariants https://buff.ly/3bP4tVe
In the United States, BA.4.6 is currently the only other variant besides BA.5 that has appreciable growth and is currently only 4.8% of of cases.
BA.4.6, BA.4.7, and BA.5.9 have additional R346 mutations.
BA.5 breakthrough-infection convalescents exhibit significant neutralization activity decrease against BA.4.6, BA.4.7, and BA.5.9.
Bebtelovimab remains potent against these subvariants, but Evusheld is completely escaped by these subvariants.
Omicron subvariants:
8/8/22 FT: BioNTech and Pfizer to begin clinical trial of vaccine for new Covid variants https://buff.ly/3vMPAJR
BioNTech/Pfizer will start a clinical trial of the BA.4 and BA.5 variants vaccine this month.
BioNTech has been manufacturing doses of its BA.1 Omicron vaccine since the spring and is ready to deliver whenever it is approved.
The company expects to be able to start delivering shots targeted at BA.4/BA.5 as early as October, if it receives regulatory approval.
The European Medicines Agency will require clinical data for a shot targeted to BA.4 and BA. 5.
The US FDA has said it would be prepared to approve the shot while trials are ongoing.
8/8/22 CDC/IDSA COVID-19 Clinician Call Confronting BA.4/BA.5: What Clinicians Can Dohttps://buff.ly/3deILdy
Doses of medications still available:
bebtelo
8/6/22 MedRxiV: COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1 subvariant predominance period https://buff.ly/3QuwJuP
Retrospective cohort study using EHR data. Patients with rebound may have been missed if they did not report it.
Rebound infections and symptoms 2-8 days after Paxlovid treatment were 32% higher in the BA.5 cohort than in the matched BA.2.12.1 cohort, although the absolute numbers were low (about 3%).
Variants can influence the likelihood of Paxlovid rebound.
8/6/22 JAMA: Examination of SARS-CoV-2 In-Class Transmission at a Large Urban University With Public Health Mandates Using Epidemiological and Genomic Methodology https://buff.ly/3Pbh96q
Boston University, Fall 2021
Mandated vaccination and indoor masking but that was otherwise fully open.
Of more than 140,000 in-person class events and a total student population of 33,000 between graduate and undergraduate students, only 9 instances of potential in-class transmission were identified, accounting for 0.0045% of all classroom meetings.
8/6/22 WSJ: Eli Lilly’s Covid-19 Antibody Treatment to Be Sold Commercially https://buff.ly/3p2gVUC
Bebtelovimab is the only monoclonal antibody left that works against BA.5. The US government supply is about to run out.
Lilly will make Bebtelovimab available for purchase by states, territories and hospitals at a list price of $2100 per dose.
8/5/22 Lancet preprint: Comparative COVID-19 Vaccines Effectiveness in Preventing Infections, Hospitalizations, and Deaths with SARS-CoV-2 BA.5 and BA.2 Omicron Lineages: A Case-Case and Cohort Study Using Electronic Health Records in Portugalhttps://buff.ly/3JC5L2u
In Portugal, comparative vaccine effectiveness of primary and booster vaccination between Omicron BA.5 and BA.2 lineages against infection and against hospitalization and mortality.
Portugal, by variant, sequenced
Via Eric Topol: Vaccinations with booster effectiveness against:
Hospitalization
BA.2 93% VE
BA.5 77% VE
Death
BA.2 94% VE
BA.5 88% VE
8/5/22 Lancet: Persistence of Long COVID somatic symptoms after COVID-19 in the Netherlands: an observational cohort study https://buff.ly/3Q59isf
SARS-CoV-2 alpha variant or previous variants. 4231 people with COVID and 8462 controls.
Prospective study of Long Covid with symptoms documented before Covid and with age and sex-matched controls
1 in 8 people (12.7%) developed Long Covid after SARS-CoV-2 infections.
8/4/22 CDC: Long COVID in Children and Adolescents — United States, March 1, 2020–January 31, 2022 https://buff.ly/3bBSjir
While absolute incidence is rare, relative 2X rate of pulmonary embolism, myocarditis, cardiomyopathy, venous thrombosis; 20-30% increased risk of Type I diabetes and kidney disease.
8/3/22 Bloomberg: New HHS Long Covid Office Aims to Advance Treatment for Patients https://buff.ly/3QqEpP4
8/3/22 Lancet preprint: Vaccine Effectiveness of BNT162b2 Against Omicron in Children Aged 5-11 Years: A Test-Negative Design https://buff.ly/3Jv27qV
High level of vaccine protection vs severe Covid outcomes in children ages 5-11 during Omicron.
8/3/22 BioRxiV: Breakthrough BA.2 variant infections elicit cross-immunity vs. BA.2.12.1 and BA.5, in contrast to BA.1, driven via N-terminal domain antibodies. https://buff.ly/3BEKhzP
8/3/22 Nature: A first update on mapping the human genetic architecture of COVID-19 - Nature https://buff.ly/3vBINCM
An update on the many (now 23) human genomic loci that influence susceptibility/protect from getting Covid infections or affect the risk of getting severe Covid, requiring hospitalization.
Genes, COVID
8/2/22 JAMA: Association of Receiving a Fourth Dose of the BNT162b Vaccine With SARS-CoV-2 Infection Among Health Care Workers in Israel https://buff.ly/3SmBubJ
@EricTopol: This is why 2nd boosters should be available for all health care workers now.
A report on ~30,000 Israeli HCWs indicates 65% lower risk of breakthrough infections during the Omicron wave with 2nd booster (4 doses vs 3 doses).
8/2/22 COVID viral rebound found in 12% people who did NOT take Paxlovid, but most did not have high viral load.
8/2/22 MedRxiV: Viral and Symptom Rebound in Untreated COVID-19 Infection https://buff.ly/3Jq8ziR
12% of participants had viral rebound.
Viral rebounders were older than non-rebounders.
Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution.
Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare (found in 1-2%).
Study limitation: mostly unvaccinated population infected with pre-Omicron variants.
8/3/22 NBC: Covid rebound can happen even in people who haven’t taken Paxlovid https://buff.ly/3SlRjQ2
Around a third of people with COVID will experience a rebound of their symptoms, regardless of whether they’ve been treated with the antiviral Paxlovid, according to a study”
27% of people with COVID saw a rebound in their symptoms after they had initially improved.”
12% of people with COVID had a ‘viral rebound,’ meaning they tested positive again several days after testing negative.”
CDC: vax + 2 boosters decreased risk of death by 96%
Why do different countries have different patterns of waves of infection?
The “Immunity Wall” of a population includes:
Age of population. Immune system of elderly doesn’t mount the same response.
Prior infections, vaccines, boosters
Immunity waning over time
Comorbidities, like obesity or diabetes
7/31/22 Japan’s unvaccinated children and teens drive record COVID infections
7/30/22 Comparative effectiveness of Pfizer BNT162b2 versus Moderna mRNA-1273 boosting in England: a cohort study in OpenSAFELY-TPP https://buff.ly/3OLVSjA
After primary vax w/Pfizer or AZ, 1.5 million people matched, Moderna v Pfizer booster, during Delta/Omicron.
Moderna booster was more effective than Pfizer for preventing infection & COVID-19 hospitalization during the first 12 weeks after vaccination.
7/30/22 Lancet: Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis https://buff.ly/3bl3pZ0
Consistent with 8 previous RCTs, Baricitinib, a JAK inhibitor, reduces death by 20% in hospitalized patients.
7/30/22 PLOS: Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2–induced lung exudative vasculitis and predicts COVID-19 severity https://buff.ly/3PTTGIk
MYL9 is a possible biomarker for COVID lung vasculitis and microthrombi.
SARS-CoV-2–induced platelet activation causes an increase in the plasma MYL9 level, which is closely correlated with clinical severity.
