Vaccine hesitancy, reactogenicity and immunogenicity of BNT162b2 and CoronaVac in pediatric patients with neuromuscular diseases (preprint)

Introduction COVID-19 causes global health and psychosocial devastation, particularly to high-risk patients such as those with neuromuscular diseases (NMDs). The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two novel COVID-19 vaccines widely used across the world that confer immune protection to healthy individuals. However, hesitancy towards COVID-19 vaccination was common for patients with NMDs early in the pandemic due to the paucity of data on the safety and efficacy in this specific patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for these patients and included the assessment of the reactogenicity and immunogenicity of these two vaccines. Methods Pediatric patients were screened from our NMD registry. For the vaccine hesitancy arm, those aged 8-18 years with no cognitive delay were invited to complete surveys in January and April 2022. For the reactogenicity and immunogenicity arm, patients aged 2-21 years were enrolled for COVID-19 vaccination between June 2021 to April 2022. Participants recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before BNT162b2 or CoronaVac and within 49 days after vaccination to measure their serological antibody responses as compared to healthy children and adolescents. Results Forty-one patients completed vaccine hesitancy surveys for both timepoints, and 22 joined our reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81-75.1, p=0.010). Pain at the injection site, fatigue and myalgia were the commonest ARs. Most ARs were mild (75.5%, n=71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of BNT162b2 or CoronaVac, although there was lower neutralization against the Omicron BA.1 variant. Discussion This study demonstrated vaccine hesitancy amongst patients with NMDs was influenced by family members and changed across time. BNT162b2 and CoronaVac were safe and immunogenic even for patients on low-dose corticosteroids. Future research is required to assess the durability of the COVID-19 vaccines, the effectiveness of booster doses and other routes of administration against emerging SARS-CoV-2 variants for these patients.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with critical COVID-19 (preprint)

Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and autoantibodies against type I IFN in another 15-20% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI:1.5-528.7, P=1.1x10-4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients 13 with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10-5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie lifethreatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Humoral and Cellular Immunogenicity and Safety of 3 Doses of CoronaVac and BNT162b2 in Young Children and Adolescents with Kidney Diseases (preprint)

Background: Patients with kidney diseases are at risk of severe complications from COVID-19, yet little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. Methods: We investigated the immunogenicity and safety of an accelerated, 3-dose primary series of COVID-19 vaccines among 64 pediatric chronic kidney disease patients (mean age 12.2; 32 male) with or without immunosuppression, dialysis, or kidney transplant. CoronaVac was given to those aged <5 years, 0.1ml BNT162b2 to those aged 5-11 years, and 0.3ml BNT162b2 to those aged 11-18 years. Results: Antibody responses including S-RBD IgG (90.9-100% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6-94.0%) were significantly elicited by 3 doses of any vaccine. T cell responses were also elicited. Weaker neutralization responses were observed among kidney transplant recipients and non-dialysis children receiving rituximab for glomerular diseases. Neutralization was reduced against Omicron BA.1 compared to wild-type (post-dose 3 sVNT% level; 84% vs 27.2%; p<0.0001). However, T cell response against Omicron BA.1 was preserved, which likely confer protection against severe COVID-19. Hybrid immunity was observed after vaccination in infected patients, as evidenced by higher Omicron BA.1 neutralization response among infected patients receiving 2 doses than those uninfected. Generally mild or moderate adverse reactions following vaccines were reported. Conclusions: Our findings support that an accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases.

Effectiveness of BNT162b2 and CoronaVac against paediatric COVID-19-associated hospitalization and moderate-to-severe disease (preprint)

Background: Vaccine effectiveness (VE) of BNT162b2 and CoronaVac against COVID-19-associated hospitalization and moderate-to-severe disease due to SARS-CoV-2 Omicron BA.2 for pediatric populations that had low exposure to prior SARS-CoV-2 variants needs to be further clarified. This can be studied from the 1.36 million vaccine doses had been administered to 766,601 of 953,400 children and adolescents in Hong Kong (HK) since March 2021 to April 2022. Methods: Using an ecological design leveraging the HK vaccination coverage statistics and public hospital records, this study investigated the VE for children aged 3-11 years and adolescents aged 12-18 years at the population level during the Omicron BA.2 wave from January to April 2022. Findings: VE against COVID-19-associated hospitalization for children was 65.3% for 1 dose of BNT162b2 and 13.0% and 86.1% for 1 and 2 doses of CoronaVac, respectively. For adolescents, VE against COVID-19-associated hospitalization was 60.2% and 82.4% after 1 and 2 doses of BNT162b2 and 30.8% and 90.7% after 1 and 2 doses of CoronaVac, respectively. Protection against moderate-to-severe disease for aged 3-18 was high, with VE of 93.1% and 95.8% after 2 doses of BNT162b2 and CoronaVac, respectively. No COVID-19-associated hospitalization or moderate-to-severe disease occurred for 68,565 children and adolescents who received their third dose. Estimated hospitalizations of children and adolescents averted by vaccination were 68 and 999, respectively, and were 45 and 147 for moderate-to-severe cases. Conclusions: BNT162b2 or CoronaVac provide substantial protection from COVID-19-associated hospitalization and moderate-to-severe disease due to a SARS-CoV-2 variant of concern. Funding: The Providence Foundation.

Antibody and T cell responses against wild-type and Omicron SARS-CoV-2 after the third dose of BNT162b2 in healthy adolescents (preprint)

High effectiveness of the third dose of BNT162b2 in healthy adolescents against Omicron BA.1 has been reported, but immune responses conferring this protection are not yet elucidated. In this analysis, our study (NCT04800133) aims to evaluate the humoral and cellular responses against wild-type and Omicron (BA.1, BA.2 and/or BA.5) SARS-CoV-2 before and after a third dose of BNT162b2 in healthy adolescents. At 6 months after 2 doses, S IgG, S IgG Fc receptor-binding, S-RBD IgG and neutralizing antibody responses waned significantly, yet neutralizing antibodies remained detectable in all tested adolescents and S IgG avidity increased from 1 month after 2 doses. The antibody responses and S-specific IFN-γ+ and IL-2+ CD8+ T cell responses were significantly boosted in healthy adolescents after a homologous third dose of BNT162b2. Compared to adults, humoral responses for the third dose were non-inferior or superior in adolescents. The S-specific IFN-γ+ and IL-2+ CD4+ and CD8+ T cell responses in adolescents and adults were comparable. Interestingly, after 3 doses, adolescents had preserved S IgG, S IgG avidity, S IgG FcγRIIIa-binding, and PRNT50 against Omicron BA.2, as well as preserved cellular responses against BA.1 S. Sera from 100% and 96% of adolescents tested at 1 and 6 months after 2 doses could also neutralize BA.1. Based on PRNT50, we predict 92%, 89% and 68% effectiveness against COVID-19 with WT, BA.2 and BA.5 1 month after 3 doses. Our study found high antibody and T cell responses, including potent cross-variant reactivity, after 3 doses of BNT162b2 vaccine in adolescents in its current formulation, suggesting that current vaccines can be protective against symptomatic Omicron disease.

Effectiveness of BNT162b2 and CoronaVac in children and adolescents against SARS-CoV-2 infection during Omicron BA.2 wave in Hong Kong (preprint)

The SARS-CoV-2 Omicron BA.2 subvariant replaced BA.1 globally in early 2022, and caused an unprecedented tsunami of cases in Hong Kong, resulting in the collapse of elimination strategy. Vaccine effectiveness (VE) of BNT162b2 and CoronaVac against BA.2 is unclear. We utilize an ecological design incorporating population-level vaccine coverage statistics and territory-wide case-level SARS-CoV-2 infection surveillance data, and investigate the VE against infection during the Omicron BA.2 wave between January 1 to April 19, 2022, in Hong Kong for children and adolescents. We estimate VE to be 33.0% for 1 dose of BNT162b2 in children aged 5–11 and 40.8% for 2 doses of CoronaVac in children aged 3–11. We also estimate 54.9% and 86.8% VE for 2 and 3 doses of BNT162b2, and 55.0% and 92.0% VE for 2 and 3 doses of CoronaVac in adolescents aged 12–18. Our findings support preserved VE against infection by variants of concerns for children and adolescents in settings with extremely low levels of prior SARS-CoV-2 circulation.

Immunogenicity and reactogenicity of SARS-CoV-2 mRNA and inactivated vaccines in healthy adolescents (preprint)

For SARS-CoV-2 vaccines, efficacy data for BNT162b2 but not CoronaVac are available in adolescents. Phase II/III studies focused on neutralizing antibody responses in adolescents, neglecting binding antibody and cellular responses that are also important against SARS-CoV-2. Therefore, we conducted a registered clinical study (NCT04800133) to establish immunobridging with various antibody and cellular immunity markers and to compare the immunogenicity and reactogenicity of these 2 vaccines in healthy adolescents. One-dose BNT162b2 outcomes were also assessed since it had been recommended in some localities due to the risk of myocarditis. Antibodies and T cell immune responses were non-inferior or similar in adolescents receiving 2 doses of BNT162b2 (BB, N=116) and CoronaVac (CC, N=123) versus adults after 2 doses of the same vaccine (BB, N=147; CC, N=141) but not in adolescents after 1 dose of BNT162b2 (B, N=116). CC induced SARS-CoV-2 nucleocapsid (N) and N C-terminal domain seroconversion in more adolescents than adults. Adverse reactions were mostly mild for both vaccines and more frequent for BNT162b2. We confirmed higher S, neutralizing, avidity and Fc receptor-binding antibody responses in adolescents receiving BB than CC. This is the first study to show similar induction of strong S-specific T cells by the 2 vaccines, in addition to N- and M-specific T cells induced by CoronaVac but not BNT162b2 in adolescents. The implications of the differential ability to induce S- and non-S-specific antibody and T cell responses on the durability of protection and protection against virus variants by BNT162b2 and CoronaVac, the 2 most used SARS-CoV-2 vaccines in the world, should be further investigated. Our results support the use of both vaccines in adolescents.

The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies (preprint)

SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.