Durability of Immunity Is Low Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1, BA.2, and BA.3 Variants After Second and Third Vaccinations in Children and Young Adults With Inflammatory Bowel Disease Receiving Biologics

The continued emergence of Omicron variants during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has challenged infection control and posed a risk to individuals with inflammatory bowel disease (IBD) despite vaccination. Previous data suggest an attenuated response to vaccination in adult patients with IBD receiving anti–tumor necrosis factor and other immunomodulatory therapy.1Vollenberg R. et al.Biomedicines. 2022; 10: 171-184Crossref PubMed Scopus (13) Google Scholar,2Jena A. et al.Clin Gastroenterol Hepatol. 2022; 20: 1456-1479Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar We previously observed a blunted antibody response in children and young adults receiving biologics after SARS-CoV-2 infection.3Dailey J. et al.Inflamm Bowel Dis. 2021; 28: 1019-1026Crossref Scopus (16) Google Scholar The Omicron variant (B.1.529.1/BA.1) became the dominant variant of concern as it spreads around the globe in November 2021.4Callaway E. Nature. 2022; 602: 556-557Crossref PubMed Scopus (40) Google Scholar Since then, subvariants of Omicron emerged (BA.2 and BA.3), each with its own set of mutations from SARS-CoV-2 infection or vaccination-induced antibodies (Supplementary Table 1).5Tang J. et al.Nat Commun. 2022; 13: 2979Crossref PubMed Scopus (10) Google Scholar,6Zahra F.T. et al.Clin Infect Dis. 2022; (Apr 21;ciac323. Online ahead of print.)PubMed Google Scholar Thus far, the BA.2 variant demonstrates higher transmissibility compared with BA.1 and has reached dominance in several countries.4Callaway E. Nature. 2022; 602: 556-557Crossref PubMed Scopus (40) Google Scholar Individuals with IBD who are receiving biologic therapies have a blunted antibody response to SARS-CoV-2 infection.3Dailey J. et al.Inflamm Bowel Dis. 2021; 28: 1019-1026Crossref Scopus (16) Google Scholar However, limited knowledge exists regarding neutralizing antibodies after 2 doses vs 3 doses of mRNA vaccination and their durability against SARS-CoV-2 Omicron lineages in children and young adults with IBD receiving therapeutics. Antibody assays were performed with approval from the US Food and Drug Administration’s Research Involving Human Subjects Committee under exemption protocol 252-Determination-CBER-2020-08-19. All assays performed fell within the permissible usages in the original consent. Study pediatric sites relied on the Connecticut Children’s Medical Center Institutional Review Board, and informed consent was obtained from at least 1 parent or legal guardian when possible, or consent was waived for deidentified samples from clinical discards. The protocol was approved by the Institutional Review Board at Connecticut Children’s Medical Center (20-073#). The study is registered on Clinicaltrials.gov (NCT04838834). In this longitudinal study, we evaluated serum samples from SARS-CoV-2 mRNA-vaccinated coronavirus disease 2019 (COVID-19)-naive IBD children and young adults aged ≥ 12 years who were receiving biologics (n = 70) vs healthy COVID-19–naive children (n = 30) for durability of the immune response after the second and third SARS-CoV-2 vaccinations (Figure 1A and B, Supplementary Table 2). Ninety-three percent of the IBD cohort was receiving infliximab and 7% vedolizumab. Virus-neutralizing titers were measured using a qualified pseudovirus neutralization assay (PsVNA) against the SARS-CoV-2 vaccine–homologous WA1 strain and against the Omicron BA.1, BA.2, and BA.3 subvariants (Supplementary Methods) The PsVNA titers correlated well with neutralization titers measured against the authentic SARS-CoV-2 in a plaque reduction neutralization test.7Tang J. et al.iScience. 2021; 24103006Google Scholar A PsVNA50 titer of 1:60 was used as a seropositive cut-off based on current understanding of neutralizing antibody titers as a correlate of protection against COVID-19.8Khoury D.S. et al.Nat Med. 2021; 27: 1205-1211Crossref PubMed Scopus (1623) Google Scholar All subjects received 2 doses of mRNA vaccine between March and December 2021, mostly Pfizer (≥97%; BNT162b2) or Moderna (mRNA-1273). All subjects received a third (or booster) vaccine dose in December 2021 to February 2022. There were no significant differences between the 2 cohorts in regard to age, sex, race, or vaccine brand (Supplementary Table 2). Children and young adults with IBD demonstrated peak SARS-CoV-2 neutralization titers at 1 month after the second vaccination (geometric mean titers [GMTs] of 315), which declined by 6-fold at 6 months after vaccination (GMTs of 57) against the vaccine-homologous WA1 strain (Figure 1C). Neutralizing antibodies after the second vaccination were minimal (GMTs < 20) against the 3 Omicron subvariants in IBD patients (Supplementary Figure 1). At 6 months after the second vaccination, the neutralizing antibody titers against WA1 and Omicron BA.1, BA.2, or BA.3 subvariants were significantly higher in the healthy children (GMTs of 106–168) compared with the IBD group (GMTs of 11) (Figure 1D). Moreover, among the IBD cohort, <5% of children had PsVNA50 above 1:60 against Omicron subvariants compared with 64%–71% for the healthy children 6 months after 2 doses of the mRNA vaccination. Importantly, a third mRNA vaccination was particularly critical to elevate the neutralizing antibodies against Omicron subvariants, especially for the IBD children and young adults (15- to 17-fold increase) (Supplementary Figure 1). At 1 month after 3 mRNA vaccinations, 73%–80% of the IBD patients demonstrated PsVNA50 greater than 1:60 against Omicron BA.1, BA.2, and BA.3 subvariants (GMTs of 168–181) (Supplementary Figure 1). By 3 months, after the third vaccination, Omicron lineage neutralizing titers in the IBD cohort (GMTs of 83–96) were 6 to 8-fold lower compared with healthy children (GMTs of 655–714) (Figure 1E). At 3 months after the third mRNA vaccination, 96% of those with IBD and 100% of healthy children showed PsVNA50 above 1:60 against vaccine-homologous WA1, whereas only 58% of the IBD cohort demonstrated PsVNA50 above 1:60 against Omicron subvariants compared with 94%–100% for the healthy children (Figure 1E). This difference in postvaccination neutralizing antibody response between the 2 cohorts were more apparent in children aged 12–18 years, wherein healthy control subjects demonstrated 25- to 42-fold higher titers (90%–100% of children with PsVNA50 above 1:60) compared with children with IBD (0% of children with IBD with PsVNA50 above 1:60) at 6 months after the second vaccination against Omicron subvariants (Supplementary Figure 2). In children with IBD, the neutralizing antibody titers increased 8- to 10-fold at 1 month after the third vaccination against the Omicron subvariants compared with 1 month after the second vaccination (Supplementary Figure 3). At 3 months after the third vaccination, neutralizing antibody titers were 4- to 6-fold higher in the healthy pediatric control subjects (aged 12–18 years) compared with children with IBD against Omicron subvariants (Supplementary Figure 2). Our study demonstrates that SARS-CoV-2 mRNA vaccines induce significantly lower short-lived cross-reactive neutralizing antibodies against Omicron lineages BA.1, BA.2, and BA.3 in children and young adults with IBD receiving biologics compared with healthy children after a second or third mRNA vaccination. As new SARS-CoV-2 variants emerge, continued determination of neutralizing antibodies after boosters will be needed in these children. One limitation of our study is the lack of children and young adults with IBD not receiving biologic therapy. Our data suggest that children, adolescents, and young adults with IBD undergoing treatment with biologic agents may benefit from a second booster dose of mRNA vaccines to provide suitable protection against the Omicron subvariants. The authors thank Keith Peden and Hana Golding for their insightful review of the manuscript, Gabrielle Grubbs for technical help, Carol Weiss for providing plasmid clones expressing SARS-CoV-2 variants, the patients and families in our infusion center for participating in the study, and Kristen Grandonico, Kristen Volz, and the Connecticut Children’s Infusion Center staff for assistance with collection and processing. Lorenza Bellusci, PhD (Formal analysis: Equal; Investigation: Equal). Fatema Tuz Zahra, PhD (Formal analysis: Equal; Investigation: Equal). Dena E. Hopkins, PhD (Methodology: Supporting; Project administration: Equal). Juan C. Salazar, MD (Conceptualization: Equal; Funding acquisition: Equal; Resources: Equal; Writing – review & editing: Equal). Jeffrey S. Hyams, MD (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Methodology: Supporting; Project administration: Equal; Supervision: Equal; Writing – original draft: Supporting; Writing – review & editing: Equal). Surender Khurana, PhD (Conceptualization: Lead; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Lead; Methodology: Lead; Project administration: Equal; Supervision: Equal; Writing – original draft: Lead; Writing – review & editing: Equal). Download .pdf (.36 MB) Help with pdf files Supplementary MaterialSupplementary Table 1. SARS-CoV-2 Variant Strain Mutations Introduced in the Spike Plasmid for Production of SARS-CoV-2 Pseudovirions for PsVNASupplementary Table 2. Demographics and Clinical Information of COVID-19–Naive Children and Young Adults With IBD Receiving Biologics and Healthy Children and Young AdultsSupplementary Figure 1. Longitudinal neutralizing antibody titers against SARS-CoV-2 omicron subvariants after second and third vaccinations in COVID-19–naive children with IBD.Supplementary Figure 2. Neutralizing antibody titers against SARS-CoV-2 omicron subvariants after second and third vaccinations in COVID-19–naive children with IBD or COVID-19–naive healthy children younger than 18 years.Supplementary Figure 3. Fold-increase in neutralizing antibody titers against SARS-CoV-2 omicron subvariants at 1 month after second and third vaccinations in COVID-19–naive children with IBD.