Episode 211 : Children, vaccination, viral dynamics and omicron
Ep 211-1: Miller describes in CID the evolution of Multisystem Inflammatory Syndrome in Children (MIS-C) linked to the first 3 COVID waves in the US (till July 2021). Overall almost 4500 children were diagnosed with MISC of whom 37 died. They show that cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time, but you can appreciate in the figure that it remains a very serious condition
Ep 211-2: Michael Levy in JAMA provides the very good news that in French adolescents MISC did NOT occur in fully vaccinated subjects: out of 33 cases in Sept-Oct 2021 O was fully vaccinated, 7 had received 1 dose and 26 were unvaccinated.
Ep 211-3: A case report of a 13 years old girl with sickle cell anemia, who presented with MISC, 2 months after full Pfizer vaccination. She had a positive serology for nucleocapsid as evidence of (past) SARS-CoV-2 infection. She recovered after treatment with intravenous immunoglobulins and steroids.
Ep 211-4: Another case report of a 12 years old boy, who presented with MISC symptoms 5 weeks after his second mRNA vaccine (first Pfizer, then Moderna). He also recovered under a similar treatment, but antibodies to nucleocapsid were not measured.
Ep 211-5: Patone medRxiv 25 Dec analyzes the myocarditis risk in England:
- Risk is lower after Adeno Astra-Zeneca as compared to Pfizer and highest for Moderna
- In people (men or women) over 40, the risk after SARS-CoV-2 infection is much higher (about 10 X) than after vaccination.
- In men under 40, the risk after infection is about 7 per million and after Pfizer in men, it is similar, but after the second Moderna dose, it is 101 per million.
- In women, the risk after infection and vaccination is similar.
- A third mRNA dose has only a risk of 2 per million (in over 40)
Ep 211-6: Dowell in Nature Immunology shows that after SARS-CoV-2 infection children have high common beta CoV (HKU-1 and OC43), but not alpha. Neutralization is robust and declines much slower than in adults.
Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal CoV.
We previously showed that the first line of defense against SARS-CoV-2, the interferon system, functions much better in children.
- MISC, the most serious complication in children, seems preventable with mRNA vaccination, with only 2 reported exceptions.
- Pfizer may be a better choice than Moderna in children, in view of myocarditis risk
- As expected, antibody and T cell responses after SARS-CoV-2 in children are more robust and sustained, but I could not find data on duration of antibody response after vaccination in children.
Effects of vaccination
Ep 211-7: Mudd in Cell analyzes draining lymph nodes of individuals vaccinated BNT162b2 mRNA vaccine and find viral spike-specific follicular helper CD4+ T cells (TfH) that persist for months and contribute to longterm immunity:
- SARS-CoV-2 vaccines induce robust human TFH responses in draining lymph nodes
- HLA-DPB1*04 (a common HLA type II) restricts the immunodominant SARS-CoV-2 S167-180 epitope
- S167-180 is recognized by T cell receptors with a public alpha chain motif
- S-specific TFH are maintained in draining lymph nodes 6 months after vaccination
Thus, mRNA vaccine has an exceptional ability to induce high-frequency antigen-specific B cell (Turner et al., 2021) and antigen-specific CD4+ TFH cell responses in the human lymph node following prime-boost administration. These characteristics underlie the development of high titer neutralizing antibodies and protection from infection in vaccinated individuals.
Ep 211-8: Another paper that points to the power of mRNA vaccine.
- Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha, Beta and Delta variants, were also efficiently generated by mRNA and continued to increase in frequency between 3 and 6 months post-vaccination.
- mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints.
Ep 211-9: EMA approval of the S protein-based vaccine by Novavax co. It was shown to be > 90 % effective against alpha variant in the US, but only 50 % against beta in South-Africa. So it will have problems with omicron too. Nevertheless, it offers a better alternative than inactivated virus for those people who are reluctant to accept mRNA vaccines. A major advantage is also that it can be stored at 4 °C.
Remember that a similar product has also been developed by the Chinese company Clover. See https://www.precisionvaccinations.com/vaccines/clover-scb-2019-covid-19-vaccine
Ep 211-10: Kissler NEJM Viral dynamics in vaccinated and unvaccinated subjects, infected with VOC:
- Overall no meaningful difference between alpha, delta and other VOC in the mean peak viral load, proliferation duration, clearance duration, or duration of acute infection.
- Breakthrough infections (BTI) among vaccine recipients were characterized by a faster clearance time than that among unvaccinated participants, with a mean of 5.5 days versus 7.5 days, whereas peak viral load was similar → infectiousness of BTI = shorter.
Ep 211-11: A very intriguing paper by Changshuo Wei in the J Genetics and Genomics (Chinese journal, impact factor 4.3): Evidence for a mouse origin of the SARS-CoV-2 Omicron variant.
The arguments are that:
- Omicron seems under a stronger positive selection than any variant, evolved in humans
- The molecular spectrum of pre-outbreak Omicron mutations is inconsistent with an evolutionary history in humans, but consistent with evolution in mice.
- Importantly, the omicron mutations overlap with those that are known to be associated with SARS-CoV-2 adaptation to mice.
- RBD mutations are expected to increase binding to mouse ACE-2 (but not experimentally confirmed, only by in silico docking)
Thus, they hypothesize that a beta VOC first got adapted to mice and then jumped back to humans.
And they predict: Given the ability of SARS-CoV-2 to jump across various species, it appears likely that global populations will face additional animal derived variants until the pandemic is under control.
Ep 211-12: Another example of high omicron infectiousness: transmission via the corridor in a designated quarantaine hotel in Hong Kong between an asymptomatic index (fully Pfizer vaccinated in June) and a secondary case (also fully Pfizer vaccinated in May), who developed respiratory symptoms and got hospitalized.
Ep 211-13: A proposal to reduce the (fixed) isolation time of 10 days after testing positive to a more “flexible” and presumably shorter isolation, by allowing people to return to society, as soon as they can show two consecutive days of negative lateral flow tests.
The question is how sensitive these tests are: in Ep 208-1, where a lower sensitivity for omicron detection was found in 7 tests.
Yesterday, FDA also issued a statement that “Early data suggests that antigen tests do detect the omicron variant but may have reduced sensitivity.”
Ep 211-14: Further epidemiological evidence of high transmissibility and short interval
Ep 211-14 A: In South-Korea the serial interval for omicron was 2.2 days, compared to Delta 3.3 days
Ep 211-14 B: In the Norway Christmas party, > 90 % of cases were fully vaccinated, the attack rate was 79 % and the interval between exposure and diagnosis was 2-4 days.
Ep 211-14 C: Nebraska outbreak of an unvaccinated and previously infected index transmitting within 3 days to all 6 household members of which 4 had been infected previously.
Implication of short interval: testing and tracing becomes more difficult to accomplish in time.
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