First a short follow-up on the previous episode (Group A Strep). A colleague pediatrician rightfully remarks that the classical “acute rheumatic fever” (ARF) has become rare in Europe, but another, possibly pathogenetically related but clinically different “Post-streptococcal Reactive Arthritis” (PSRA) is seen more. Some characteristics:
- PSRA has a bimodal age distribution at ages 8-14 and 21-37 years.
- PSRA is an asymmetrical non-migratory polyarthritis, while ARF may be migratory.
- PSRA can have extra-articular features, including erythema nodosum, uveitis and glomerulonephritis, but no cardiac involvement, the latter typical for ARF.
- It tends to occur within 10 days of a GAS infection, as opposed to the 2 to 3 weeks delay for ARF.
- Most PSRA cases resolve spontaneously within a few weeks, but PSRA can be prolonged or recurrent, in contrast to ARF, in which arthritis usually lasts a few days to 3 weeks.
- Treatment with non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids is similar.
See Ep 309-1 (sorry only abstracts, as I have no direct access rheumatological journals)
The present episode is focusing in Par 1 on meta-analyses of SARS-CoV-2 risk in pregnant women, the epidemiology and the beneficial effect of vaccination in children. In Par 2, a very nice overview on variants is discussed as well as the observed and predicted risk of novel variants in India and Europe respectively.
Par 1: Meta-analyses on mothers and children
Ep 309-2: Emily Smiths BMJ Global Health Jan 2023 Extensive review on maternal and neonatal risks
SARS-CoV-2 infection at any time during pregnancy increases the risk of
- maternal death, severe maternal morbidities and
- neonatal morbidity, but not stillbirth or intrauterine growth restriction.
Ep 309-3: Reza Naeimi eClinicalMedicine The Lancet Feb 2023: SARS-CoV-2 seroprevalence in children worldwide before Omicron
- Seroprevalence estimates varied from 7.3% (5.8–9.1%) in the first wave to 37.6% (18.1–59.4%) in the fifth wave and 56.6% (52.8–60.5%) in the sixth wave.
- Highest seroprevalences were estimated for South-East Asia (17.9–81.8%) and African (17.2–66.1%) regions; while the lowest seroprevalence Western Pacific region (0.01–1.01%).
- Seroprevalence estimates were higher in children at older ages, in those living in underprivileged countries or regions, and in those of minority ethnic backgrounds.
Ep 309-4: Dan-Yu Lin medRxiv 19 Jan Effectiveness of vaccination and previous infection against Omicron infection and severe disease in children North Carolina up to Jan 6th 2023
Covering delta (grey); BA.1 (light blue), BA.2 coral) BA.4 (green), BA.5 (purple), BQ.1/BQ.1.1 (yellow), XBB/XBB.1.5 (brown),
For children 5-11 years:
- VE of primary vaccination against infection: 60 % (Mo1) 33.7 % (Mo4) 15 % (Mo 10)
- VE of booster against infection: only after Mo1
- Monovalent 24.4 %
- BA.5 bivalent 75.7 %
- Effect of omicron infection on prevention of reinfection: 80 % (Mo 3) and 54 % (Mo 6)
For children 0-4 years:
- VE primary vaccination against infection: 64 % (Mo 2) and 58 % (Mo 5)
- Effect of omicron infection on reinfection: 77 % (Mo 3) and 64.7 % (Mo 6)
For all ages vaccination + previous infection: more effective against hospitalization and death than against infection.
- Some confidence intervals are very wide, especially protection against hospitalization and death: maybe due to low numbers of children with severe disease?
- VE in children under 12 years were lower than those of adults and adolescents previously reported. However:
- Administered in children under the age of 12 years much later than in adults and adolescents and the emergence of recent variants reduced VE.
- Dosages for children under 12 years of age were lower than those of older individuals.
- High effectiveness of bivalent booster against infection clearly limited in time: wanes very rapidly: because of emergence of highly immune escaping variants at the end of 2022- beginning of 2023?
- Vaccination provided additional protection for previously infected children, and omicron infection induced strong immunity in both vaccinated and unvaccinated children
PAR 2 VARIANTS
Ep 309-5: Carabelli Nat Rev Microbiol Jan 2023 : Nice review on the origin of recombinant SARS-CoV-2 viruses and the various characteristics of variants
A phylogenetic tree from April 2022 shows how different Omicron is
And the more recent complex evolution within Omicron is illustrated on the Johns Hopkins website
The lack of intermediate sequences (e.g. between WT and Omicron) has led to several hypotheses
(1) circulation in geographically undersampled regions;
(2) cryptic circulation within an animal reservoir (e.g. farmed mink and whitetailed deer) following reverse zoonosis of an early variant;
(3) evolution within a chronic infection in an immunosuppressed host or multiple human hosts.
→ Chronic infection hypothesis’ is the best supported of these scenarios: can drive mutational profiles highly similar to those of VOC.
In the figures below, various recombinant viruses between delta and omicron, as well as intra-omicron recombinants are illustrated.
Out of these, XBB descendants XBB.1 and XBB.1.5 are the most succesfull
Below: Properties of amino acid substitutions or deletions in selected SARS-CoV-2 variants of concern (VOC)
- First column to the left: Black boxes denote the presence of each mutation in the variant of concern.
- Second column: Epitope residues are colored to indicate two binding sites for binding of neutralizing antibodies (neut Ab) (1) the amino-terminal domain (NTD) supersite or (2) the various sites within the receptor-binding domain (RBD)
- Third: Deep Mutational Scanning (DMS) of RBD residues show the escape fraction (the extent to which a mutation reduced polyclonal antibody binding) averaged across plasma (‘plasma avg’) and for the most sensitive plasma
(‘plasma max’). Plasma is from infected convalescent people.
- Fourth: Mutations in the furin cleavage site are highlighted. This is the site where S1 and S2 are cleaved by cellular enzymes to expose the fusion peptide, thus enhancing fusion with cell membrane. .
- Fifth: Orange shading indicates the distance to angiotensin-converting enzyme 2 (ACE2)-contacting residues that form the receptor-binding site (RBS).
- Sixth: ACE2-binding scores representing the binding constant (Δlog10 KD) relative to the wild-type reference amino acid from DMS experiments are shown in shades of red or blue
The “convergent evolution” is quite evident: many mutations, especially in RBS and furin cleavage site.
Most mutations result in immune escape (3rd column) and/or enhance binding of RBS to ACE-2 receptor (6th column).
Furin cleavage site (FCS) optimization during evolution
a, Comparison of S1–S2 cleavage site sequences in wild-type (WT) SARS-CoV-2 and Alpha, Delta and Omicron VOC compared with other coronaviruses: SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) as well as the 4 “common cold” human coronavirus OC43 (HCoV-OC43), HCoV-HKU1, HCoV-NL63 and HCoV-229E.
b. Diagrammatic representation of estimated relative optimization of the S1–S2 furin cleavage site (FCS) for the variants of concern. The mutations affecting FCS function are indicated
Potential impact of SARS-CoV-2 variants on T cell responses
a, Following SARS-CoV-2 infection, CD4+ T cell and CD8+ T cell responses are generated against 30–40 epitopes across the virus genome (epitopes are shown in red and blue).
b, An example of how an amino acid change within one epitope might impact epitope-specific cytotoxic T cell responses, thereby inhibiting the elimination of virus-infected cells. T cell evasion of SARS-CoV-2 has been shown to be the consequence of impaired peptide binding to the major histocompatibility complex (MHC) or poor binding of the T cell receptor (TCR) to the peptide–MHC complex.
c, Although the T cell response to vaccination is focused on the spike protein alone, even the multiple spike mutations in the Omicron variant of concern reduce the vaccine-induced spike-specific T cell response only by less than 30%, with considerable interindividual variability
M, membrane protein; N, nucleocapsid protein.
Dominant SARS-CoV-2 variants, vaccinations, infections and deaths since early 2020 in the UK
a, Waves of dominant variants in the UK (B.1, B.1.1.7/Alpha, B.1.617.2/Delta, AY.4.2/Delta and Omicron sublineages BA.1, BA.2, BA.4 and BA.5), proportion of the UK population with one or two doses and with one booster vaccination, number of COVID-19 cases and number of reported COVID-19-related deaths: Vaccination + Omicron clearly associated with less deaths
b, Diagrammatic visualization of the dynamic relationship between variant transmissibility, antigenicity, virulence and fitness. As population immunity derived from infection and vaccination increases, the fraction of completely immunologically naive hosts declines (gradient blue lines). Consequently, the importance of antigenic novelty in determining variant fitness increases.
Antigenic distance to previously circulating variants becomes an increasingly key determinant of variant transmissibility, increasing the potential for intrinsic and real-world transmissibility to diverge.
Similarly, antigenic distance influences a variant’s potential to infect and cause disease in immune hosts, increasing the potential for a variant’s intrinsic virulence to diverge from its real-world clinical impact both in terms of transmission and disease severity, which may evolve in different directions, as we see: Omicron is more transmissible and less pathogenic in a population with high level of infection- and/or vaccination-induced immunity.
Ep 309-6: ECDC predictions on XBB.1.5 as of 13 Jan 2023
- Moderate probability of XBB.1.5 becoming dominant in the EU/EEA and causing a substantial increase in the number of cases of COVID-19: after one to two months given the current reported proportions of XBB.1.5 in the EU/EEA and its estimated growth rate. Due to the heterogeneity of former COVID-19 waves, differences in vaccine uptake and population immunity, etc. XBB.1.5 may spread differently in different countries.
- Infection in the general population is expected to have a low impact, due to low incidence of severe disease with the Omicron VOC and prior immunity (either through vaccination, prior infection or both).
- In vulnerable populations (immunocompromised, comorbidities and/or 65+):
- Moderate impact if recent COVID vaccine received
- High impact if incompletely vaccinated.
Ep 309-7: Rajesh Karyakarte medRxiv 6 Jan 2023: Outcome of Omicron subvariants and XBB infections in India.
BA.32.75 and XBB* variant are causing rather mild disease in India (as compared to Delta)
18 Feb 2023 Episode 316: Under which circumstances could type I or type III IFN be a useful treatment?
> More info