16 March 20222 Episode 249: Controversy on immune response in children; follow-up on vaccination and pathophysiology

Dear colleagues,

Par 1 Controversy about  adaptive immune response in children after infection

Ep 249-1: Toh JAMA March 2022 Seroconversion in children lower than in adults. 

From Household study  in first wave (May-Oct 2020).  Children (2-10 yrs interquartile)

Lower seroconversion (measured in convalescence phase):

• Not associated with viral load  in acute phase= similar see Fig 3 B
• Not associated with age and sex of children.

As could be expected, individuals were more likely to be seropositive with higher viral loads and longer viral clearance time during acute phase (but there were no differences in these parameters between children and adults who were seronegative (Fig 3 C)

Adults who remained ASY more likely to stay seronegative, but not so on children (Fig 3 D)

Conclusion: Among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads.

Interpretation: Children manage the virus quickly by innate immune system (type 1 IFN) → the virus fails to trigger the adaptive immune response?

Ep 249-2 (= 172-5): Weisberg Nat Immunol Nov 2020 (first wave) Ab responses in 4 cohorts

• Adults recruited as convalescent plasma donors (CPDs) who recovered from mild COVID-19  (CPD, n = 19),
• Adults hospitalized with severe COVID-19 ARDS (COVID-ARDS, n = 13)

• Children hospitalized with MIS-C (MIS-C, n = 16) and
• Children who were infected with SARS-CoV-2, were hospitalized but did not develop MIS-C  (pediatric non-MIS-C, n = 31)

Clearly, adult ARDS patients have highest anti-S IgG (a), neut Ab (b) and positive anti-Nucleocapsid (d)

Children have lower neut Ab (b) and much lower N-Ab (d), with no difference between MISC and non-MISC

Ep 249-3 (= 194-11):  Durability of anti-nucleoprotein Ab (N-test) in children (5-19 years old) of Texas (Oct 2020)

There was no difference in the presence of antibodies by symptom status (asymptotic versus symptomatic) or severity (mild-moderate versus severe), sex, age group, or body mass index group (underweight, healthy weight, overweight, obesity) over the three antibody measurement timepoints (each 2-3 months apart.

Episode 249-4 (= Ep 211-6): Dowell in Nature Immunology Children develop robust and sustained cross-reactive spike-specific immune responses to SARS-CoV-2 infection

Children (3-11 yrs) and adults with mild infection June 2020 (first wave)

1. Higher antibodies against Spike (including against RBD and NTD) in children than in adults

Fig. 1 | Children and adults develop coordinated antibody responses to SARS-CoV-2: SARS-CoV-2 antibody levels measured by MSD assay in children (n = 91) and adults (n = 154). Serostatus was assigned based on spike serology and used to divide the cohorts into seropositive (red for children/blue for adults) and seronegative (light red/light blue) (seropositive/negative children n = 43/48, adults n = 91/63, respectively)

→ In  this study: Ab in children higher than in adults (ratio children/adults 1.4 for S Ab; 1.1 for N Ab ; 1.7 for receptor binding domain (RBD) Ab and 2.3 for N-Terminal Domain (NTD) Ab  

2.  Antibodies against seasonal beta CoV (but not alpha) are boosted in children but not in aduls

Fig 2 Antibody titers to the seasonal hCoV coronaviruses in children (red) and adults (blue) based on SARS-CoV-2 serostatus (dark, seropositive, light, seronegative;

3. Neutralization is robust and declines much slower than in adults.

Fig. 6 | Superior antibody binding of SARS-CoV-2 variants in children and comparable neutralization

4. 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. 

Fig 4: Spike-specific T cell responses in SARS-CoV-2 seropositive and seronegative children. a, SARS-CoV-2-specific T cell responses in children (n = 57, red) and adults (n = 83, blue) based on SARS-CoV-2 serostatus (dark; seropositive, light; seronegative). SARS-CoV-2 serostatus was 37/20 seropositive or negative in children and 64/29 seropositive or negative in adults, respectively. The assay used IFN-γ ELISpot using pepmixes containing overlapping peptides to spike, Nucleocapsid/Membranre or influenza and is shown in relation to serostatus

5. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months

Fig. 5 | Immune responses are maintained in children at least six months after infection. a, Antibody responses in children (n = 35, red) and adults (n = 81, blue) who were seropositive at first testing and therefore at least 6 months post-primary infection. The bars indicate the GMT ± 95% CI. The dotted lines indicate seropositive cutoffs. Fold change indicates increment in children’s GMT compared to adults. The black dots indicate individuals who were seronegative for spike but retained a nucleocapsid-specific antibody response.

Ep 249-4: Kaaijk Fron Imm Feb 2022 Dynamics of  T cell responses up to 10 months after infection in children and adults

Household study in first wave (May-Oct 2020):

• Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children.

Spike specific T cell responses                                  Nucleocapsid T cell responses

T1= 8 days post-symptoms (PS);  T2 = 3 weeks PS;  T3 = 5-7 weeks PS; T4 = 10 months PS

• The S-SARS-CoV-2 IFN-g T cell response correlated with S1-SARS-CoV-2-specific serum antibody concentration

• Frequencies of SARS-CoV-2-specific T cells were significantly reduced at 10 months after symptom onset, while S1-SARS-CoV-2-specific IgG concentrations were still detectable in 90% of all children and adults

CONCLUSION:   

First, there is no doubt that children in general cope better with SARS-CoV-2 than adults.  The main reason is their very “alert” type 1 interferon system, as we have repeatedly discussed before.  But How well is their “adaptive” immune system (T and B cells) coping with the virus?  

The starting point of this analysis was a paper in Nature Briefing 10 March (Ep 249-6), entitled Kids show mysteriously low levels of COVID antibodies (after infection).  It was based on the former two recent papers (Toh Ep 249-1 and Weisberg Ep 249-2).   It is quite evident that this claim is not universally true, especially Dowell 249-4 goes into the opposite direction: rather higher and well sustained Ab and T cell responses in children as compared to adults. 

• All papers refer to the first wave, so the virus is similar. In 249-1, it is also shown that the viral load is similar.
• The age distribution of children in the various studies may be different, but not clear if that has an influence.
• Children in Weisberg (249-2) are hospitalized, while in the other studies they had mild infection.  Since there is a discrepancy between the results after “mild disease” in Ep 249-1 and Ep 249-5 versus Ep 249-4, disease severity is not the explanation.
• Unlikely that technical issues play a role: as long as you compare children and adults with the same assay.
• Household  studies (Ep249-1 and -5)  may be better controlled than the others and go into the same direction of weaker responses in children than adults.  

So, although there is an unexplained discrepancy in the data,  most evidence seem to point to a somewhat weaker T and B response in children, maybe as a consequence of milder disease and shorter exposure to the virus.  To what extent this will translate in more frequent reinfection remains to be determined

Par 2 Follow-up on vaccination results

Ep 249-7 : Molteni medRxiv 13 March 2022 analyzes aspects of vaccination in a large cohort of 12-17 years old in England.  Comparing about 26,000 vaccinated vs 75,000 unvaccinated.

Risk of symptomatic infection after (at least) one dose of Pfizer:

• For Delta: -80·4% and -61.5 %  at 14–30 days and 61-90 days
• For omicron respectively -53.7 and - 63.7 %
• Risk is further reduced if infected before vaccination:
  • no infection documented in delta  period
  • not clear for omicron period

Most symptoms clearly milder if they  occur  after vaccination, especially with Delta

Side effects: mild local and systemic side-effects very common (60 %), especially after second dose

Very few hospitalizations (0.1 %) after vaccination: 2 diagnoses of Guillain-Barré; no formal diagnosis of myocarditis, but suggestive symptoms in 0.3 %.

All side-effects transient.

Ep 249-8: UK Health Security Agency 10 March 2022: Update on vaccine surveillance

1. Protection against symptomatic infection

Confirmation that primary vaccination with Pfizer is superior and third dose with Moderna also superior

2. Vaccine effectiveness against hospitalization remains 80 % after 3rd Pfizer dose and 90 % after 3rd Moderna

3. Similar efficiency against BA.1 and BA.2:

4. Effect on pregnancy outcome (see p. 29-33) NS lower prevalence of low birthweight and stillbirth in vaccinated vs unvaccinated women.   Tentative explanation: high risk women were preferentially vaccinated.

Ep 249-9: Baum medRxiv 13 March 2022 Very similar encouraging data amongst elderly (70+)  in Finland

Note: Cominaty = Pfizer-BioNtech; Spikevax = Moderna; Vaxzevria = Astra-Zeneca

Par 3 Pathophysiology

Ep 249-10: Kousathanas Nature 23 Feb  New genetic markers of severe COVID, linked to:

• Interferon regulation (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2);  
• Reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1);
• Myeloid cell adhesion molecules (SELE, ICAM5, CD209) and coagulation factor F8.

Author’s conclusion: These genetic associations implicate new biological mechanisms underlying the development of life-threatening Covid-19, several of which may be amenable to therapeutic targeting

However, as explained in Ep 249-11, this translation from genetic association to new therapeutic approaches is not as straightforward as we would wish: see the clear association of severe COVID with type 1 IFN dysfunction, yet the failure to treat COVID with IFN….   

Ep 249-12 and -13: Hester Allen in medRxiv and Smiti Mallapaty in Nature Briefing, how Omicron overtook Delta with very nice figures.  Conclusions similar as in Denmark:

• Elevated secondary attack rates for Omicron vs Delta in household (15.0% vs 10.8%) and non-household (8.2% vs 3.7%) settings.
• Transmission in households was significantly less likely from cases or contacts, in receipt of three compared to two vaccine doses, but this effect was less pronounced for Omicron (aRR 0.78 and 0.88) compared to Delta (aRR 0.62 and 0.68).
• In non-household settings, a similar reduction was observed for Delta cases and contacts (aRR 0.84 and 0.51) but only for Omicron contacts (aRR 0.76, 95% CI: 0.58-0.93) and not cases in receipt of three vs two doses (aRR 0.95, 0.77-1.16).