16 May 2021 Episode 140 Vaccination in children; Immune and Viral persistence: delaying the second dose

Dear colleagues,

Today, I will try and update you on the desirability to vaccinate children, the persistence of immune responses after infection, some emerging differences with immunity after vaccination and arguments for delaying the second vaccine dose.

“Executive summary”:

1. Vaccination of children is now seen as advisable and recommended by CDC from 12 years on.
2. A wealth of data indicates both B and T cell responses after symptomatic infection is durable up to > 9 months. However, asymptomatic infection results in rapid waning.  No evidence that pre-existing SARS-CoV-2 specific T cells protect against disease.
3. Viral persistence in children with ALL, but also emerging evidence that loss of taste and smell may be linked to local viral persistence.  
4. Vaccination of previously infected subjects results not only in higher antibody responses, but also qualitative differences, including potent neut of B.1.315 (South-African variant).
5. Emerging evidence of mucosal T cell involvement in vaccine effect.
6. Delaying a second dose may be favorable mainly in < 65 yrs old, if first dose efficacy is high (mRNA vaccines), rate of vaccination is low and significant risk of infection 1% is present.   

SARS-CoV-2 vaccination in children: there is a clear-cut evolution over the last year

Ep 140-1: Christiane Eberhardt in Pediatr Allergy Immunol is still very hesitant, because she feels that the incidence and disease severity of COVID-19 are low in children, and despite their infectiveness, their role in disease propagation is limited.  Therefore: safety is paramount, since vaccination should not be primarily performed for their self-protection but for that of the community, mainly the elderly or high-risk individuals.

She adds that COVID has jeopardized regular vaccinations in children and that is more concerning.

Ep 140-2: Carol Kao et al in Clin Infect Dis are more convinced of childhood vaccination, because: 

• The disease burden by COVID in children may be underestimated.
• Similar to other infectious diseases such as Rubella, Rotavirus, Streptococcus pneumonia, community protection against COVID will only occur after childhood vaccination.

Ep 140-3:  Petersen and Buchy are even more convinced and they explicitly refer to the increasing infectiousness of novel variants, implying that vaccinating children will be needed to limit their circulation in the population. They do refer specifically also to Africa, where a large part of the population is below 20 years old.  They also refer to ongoing trials with the mRNA as well as J&J vaccine in children.

Ep 140-4: On May 12, CDC has issued a formal recommendation to vaccinate everyone > 12 years to help protect against COVID-19.  

Durability of B and T cell responses after natural infection

Ep 140-5: Cohen in medRxiv April: over 250 COVID patients (71% mild, 24 % moderate and 5 % severe with median 48.5 yrs old) followed over 8 months:

• Antibodies against S and RBD (p. 51) slow biphasic decay with half-life IgG and IgA  > 200 days; IgM 100 days.
• Similarly Neut Ab also long half life (p. 53). Remarkably severe> moderate> mild (p. 57)
• Memory B cells rather stable (p. 54)
• Polyfunctional CD4 and CD8 T cells, withCD4 T cells targeting various proteins and CD8 T cells mainly focusing on N (p.55-56)

Ep 140-6: Lin Yao in J Infect Dis: 59 pt (38 moderate, 16 mild and 5 asy; medial 42 yrs) over 9 months

• 90% of patients still have detectable IgG antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus. (p. 22)
• SARS-CoV-2-specific IgG+ memory B cell and IFN-γ secreting T cell responses were detectable in over 70% of patients (p.23).
• No significant difference between mild/asymptomatic versus moderate.

Ep 140-7: Sherina in Med (Cell Press): very similar results in 88 pt over 6 months

• Anti-SARS-CoV-2 antibodies were present in the majority of COVID-19 patient samples.
• RBD- and S-specific IgG levels remained stable up to 6 months after diagnosis.
• Specific memory B and T cells developed in >95% of COVID-19 patients.
• Memory B and T cell responses were maintained at least 6–8 months after infection

Ep 140-8: Zhiwei Sui in Signal Transduction and Targeted Therapy compares 143 asymptomatic with 43 patients with “persistent” infection (> 30 days).  Not surprisingly, the former are younger, more female, have a low viral load and less underlying disease.  The important message here is that asymptomatic individuals have only temporary positive antibody levels  against N+S (apparently not distinguished): “diminishing time” estimated at 67 days. 

This study is not very clear methodologically and limited to serum antibodies (no memory B or T cells), but emphasizes that mild infection could be not enough for lasting protection. 

Ep 140-9: Casado in JID on a cohort of 22 HCW: median 34 yrs with asymptomatic or mild disease:

• A correlation between low initial antibody and T cell responses as well as low initial responses and rapid decline
• As many as 27% of convalescent HCWs have lost specific antibodies as early as 2 months, a rate that increased to 41% at 5 months.

Ep 140-10: Casado in Clin Microbiol Infect. show that pre-existing CD8 T cell responses against various peptides (in S, M, N) do not protect against incident SARS-CoV-2 infection.

Viral persistence?

Ep 140-11: de Melo in Sc Transl Med suggesting that SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell. 

This conclusion is based on histological and molecular investigation of patient material and also experiments in hamsters, but I could not get the full paper.

Ep 140-12: Truong described 3 pediatric patients with acute lymphoblastic leukemia and a persistent SARS-CoV-2 infection for up to 162 days.  Weak and atypical antibody responses were seen, as well as viral evolution with spike mutations such as delta70, delta 140-145, N440K, E484Q, which are similar or identical those previously observed in adult immune deficient patients and also in several variants of concern (British, South-African, Brazilian, Indian).

Response to vaccination

1. Difference between naïve and COVID recovered subjects:

Ep 140-13: Goel in Science Immunology: as we know, COVID recovered subjects have already a full response after 1 dose of mRNA vaccine.  Moreover, COVID recovered subjects show similar neutralization against B.1.315 (South-African) as against D614G (vaccine strain), already after 1st dose, while sera from naïve subjects have a weaker neut response against B.1.315, even after 2nd dose. (p.12)

Ep 140-14:  Vaquero in medRxiv make similar observations, with regard to amounts and subclass distribution, but do not show results of neut tests.

2.  Effect on mucosal tissue

Ep 140-15: Ssemanganda very elegantly shows that upon mRNA vaccination, there is a redistribution between peripheral blood and nasal mucosa especially of CD8 T cells with a phenotype of tissue residence (CD69+ CD109+) and also of CD4 T cells with Th17 characteristics. These CD8 T cells do respond to S peptide stimulation, but they do not correlate with serum Spike antibodies.

3. Arguments for delaying the second Pfizer dose

Ep 140-16: A Nature Editorial states that in over 80 yrs old British: Peak antibody levels were 3.5 times higher in those who waited 12 weeks for their booster shot than were those in people who waited only 3 weeks. Peak T-cell response was lower in those with the extended interval. But this did not cause antibody levels to decline more quickly over the nine weeks after the booster shot.

Ep 140-17: Romero-Bruffau et al. investigates the effect on mortality of delaying a second dose of the COVID vaccines by modeling.  The main variables are the efficacy of the vaccine after the first dose, the rate of vaccination and the age (below or above 65).  The infection rate is fixed at 1 %.  Strange enough, I cannot find in the text how long exactly the delay is….?

Anyhow, what they show is a favorable effect of delaying on mortality if:

• The vaccine efficacy is high: at or over 80 %
• The rate of vaccination is low: at or 0.3 %) and with vaccine efficacy at 80 %.
• For people under 65 (with lower mortality risk), the delayed strategy performed equally well under all rates, with vaccine efficacy at 80 %. 

Clearly, as the mRNA vaccines have a first dose efficacy > 80 % while the Adenoviral (and inactivated vaccines are (much) less efficacious, delaying is only beneficial for the mRNA vaccines.

Even for those vaccines, it is most indicated for people below 65 and in case of limited supply (low vaccination rate).      

Ep 140-18: Wolf et al clarify a number of considerations and precautions to be taken, before deciding to change the recommended dosing schedule.

Best wishes,

Guido