Long-term real-world protection afforded by third mRNA doses against symptomatic SARS-COV-2 infections, COVID-19-related emergency attendances and hospitalizations amongst older Singaporeans during an Omicron XBB wave.

BACKGROUND: Literature on long-term real-world vaccine effectiveness of SARS-CoV-2 booster vaccines (up to and beyond 360 days) is scarce. We report estimates of protection against symptomatic infection, emergency department (ED) attendances and hospitalizations up to and beyond 360 days post-receipt of booster mRNA vaccines amongst Singaporeans aged ≥60 years during an Omicron XBB wave. METHODS: We conducted a population-based cohort study including all Singaporeans aged ≥60 years with no documented prior SARS-CoV-2 infection who had previously received ≥3 doses of mRNA vaccines (BNT162b2/mRNA-1273), over a 4-month period during transmission of Omicron XBB. We reported the adjusted incidence-rate-ratio (IRR) for symptomatic infections, ED attendances and hospitalizations at different time-intervals from both first and second boosters, using Poisson regression; with the reference group being those who received their first booster 90 to 179 days prior. RESULTS: 506,856 boosted adults were included, contributing 55,846,165 person-days of observation. Protection against symptomatic infections among those who received a third vaccine dose (first booster) waned after 180 days with increasing adjusted IRRs; however, protection against ED attendances and hospitalizations held up, with comparable adjusted IRRs with increasing time from third vaccine doses [≥360 days from third dose: adjusted IRR (ED attendances) = 0.73, 95%CI = 0.62-0.85; adjusted IRR (hospitalization) = 0.58, 95%CI = 0.49-0.70]. CONCLUSIONS: Our results highlight the benefit of a booster dose in reducing ED attendances and hospitalizations amongst older adults aged ≥60 years with no documented prior SARS-CoV-2 infection, during an Omicron XBB wave; up to and beyond 360 days post-booster. A second booster provided further reduction.

BNT162b2 vaccine protection against omicron and effect of previous infection variant and vaccination sequence among children and adolescents in Singapore: a population-based cohort study.

BACKGROUND: Information on variant-specific vaccine protection and the effect of previous infection variant is scarce in children. We aimed to ascertain the level of protection conferred by BNT162b2 COVID-19 vaccination against omicron variant infection (BA.4 or BA.5, and XBB) in a previously infected national paediatric cohort. We also explored the association between sequence of previous infection (variant) and vaccination on protection. METHODS: We did a retrospective, population-based cohort study using the national databases of all confirmed SARS-CoV-2 infections, vaccines administered, and demographic records maintained by the Ministry of Health, Singapore. The study cohort consisted of children aged 5-11 years and adolescents aged 12-17 years who had a previous SARS-CoV-2 infection from Jan 1, 2020, to Dec 15, 2022. People who were infected during the pre-delta period or were immunocompromised (received three vaccination doses [children 5-11 years old] and four vaccinations doses [adolescents 12-17 years old]) were excluded. Those who had multiple episodes of infection before the study start date, were not vaccinated before infection but completed three doses, received bivalent mRNA vaccine, or received non-mRNA vaccine doses were also excluded. All SARS-CoV-2 infections confirmed by reverse transcriptase polymerase chain reaction or rapid antigen testing were grouped into delta, BA.1, BA.2, BA.4 or BA.5, or XBB variants using a combination of whole-genome sequencing, S-gene target failure results, and imputation. For BA.4 or BA.5, the study outcome period was June 1-Sept 30, 2022, and for XBB variants the outcome period was Oct 18-Dec 15, 2022. Incidence rate ratios between vaccinated and unvaccinated were derived using adjusted Poisson regressions and vaccine effectiveness was estimated as (1-risk ratio) × 100%. FINDINGS: 135 197 people aged 5-17 years (79 332 children and 55 865 adolescents) were included in the cohort for the vaccine effectiveness analysis against omicron BA.4 or BA.5, and 164 704 people aged 5-17 years (97 235 children and 67 469 adolescents) were included for the analysis against omicron XBB. Approximately 47% of participants were female and 53% were male. Among those previously infected, vaccine effectiveness against BA.4 or BA.5 infection in fully vaccinated children (two doses) was 74·0% (95% CI 67·7-79·1) and in adolescents (three doses) was 85·7% (80·2-89·6). Against XBB, protection conferred with full vaccination was lower at 62·8% (95% CI 42·3-76·0) in children and 47·9% (20·2-66·1) in adolescents. In children, receipt of two-dose vaccination before first SARS-CoV-2 infection provided them with the highest protection against subsequent BA.4 or BA.5 infection at 85·3% (95% CI 80·2-89·1); however, this was not shown to be the case for adolescents. First infection variant had an effect on vaccine effectiveness against omicron BA.4 or BA.5 reinfection in the following descending order: BA.2 conferred the highest protection (92·3% [95% CI 88·9-94·7] in children and 96·4% [93·5-98·0] in adolescents) followed by BA.1 (81·9% [75·9-86·4] in children and 95·0% [91·6-97·0] in adolescents), and delta which conferred the lowest protection (51·9% [5·3-75·6] in children and 77·5% [63·9-86·0] in adolescents). INTERPRETATION: In previously infected children and adolescents, BNT162b2 vaccination provided additional protection against omicron BA.4 or BA.5 and XBB variants compared with those who remained unvaccinated. Hybrid immunity against XBB was lower than against BA.4 or BA.5, especially in adolescents. Early vaccination of previously uninfected children before their first SARS-CoV-2 exposure could potentially strengthen population immunity resilience against future variants. FUNDING: None.

Protective immunity of SARS-CoV-2 infection and vaccines against medically attended symptomatic omicron BA.4, BA.5, and XBB reinfections in Singapore: a national cohort study.

BACKGROUND: Despite a large proportion of the population having been vaccinated and infected, Singapore had SARS-CoV-2 waves driven by the BA.5 and XBB sublineages of the omicron (B.1.1.529) variant. Data on the protective immunity against medically attended, symptomatic reinfections with omicron BA.4, BA.5, and XBB conferred by previous SARS-CoV-2 infections and vaccinations are scarce. We therefore aimed to derive information from Singapore's experience as one of the first countries with an XBB-driven wave. METHODS: For this retrospective national cohort study, we used information from official databases of the Ministry of Health of Singapore to assess hybrid immunity (obtained from previous infection and vaccination) against medically attended, symptomatic BA.4 and BA.5 reinfections from Oct 1, 2022, to Nov 1, 2022, and medically attended, symptomatic XBB reinfections from Oct 18, 2022, to Nov 1, 2022, among Singapore citizens and permanent residents aged at least 18 years. All individuals with acute respiratory symptoms who presented at any health-care facility in Singapore between the stated dates were tested for SARS-CoV-2. Individuals were grouped into SARS-CoV-2-naive, pre-omicron, omicron BA.1, and omicron BA.2 groups according to their previous infection status. Data were also stratified by time from first infection to analyse the waning of immunity. Incidence rate ratios (IRRs) were measured by generalised linear Poisson regressions, with SARS-CoV-2-naive individuals as the reference group, and protective immunity was calculated as one minus the risk ratio multiplied by 100. FINDINGS: 2 456 791 individuals were included in the study, contributing 53·1 million person-days of observation for the SARS-CoV-2-naive group, 3·4 million person-days for the pre-omicron group, 6·6 million person-days for the BA.1 group, and 13·7 million person-days for the BA.2 group between Oct 1, 2022, and Nov 1, 2022. Compared with SARS-CoV-2-naive individuals, first infections with pre-omicron variants did not confer protection against reinfection with BA.4 or BA.5 (IRR 0·87 [95% CI 0·73-1·05] for pre-omicron infection with booster vaccination) or XBB (IRR 1·29 [1·23-1·35] for pre-omicron infection with booster vaccination). Previous BA.2 infection with booster provided the greatest protection against reinfection, but this was lower against reinfection with XBB (protective immunity 51%; 95% CI 49-53) than against reinfection with BA.4 or BA.5 (78%; 74-82). Protection conferred by previous BA.2 infection against XBB reinfection waned faster over time from first infection (from 74% [72-75] at 3-6 months to 49% [47-52] at 7-8 months) than protection against BA.4 or BA.5 reinfection (from 87% [82-90] at 3-6 months to 74% [66-80] at 7-8 months). INTERPRETATION: Protection against XBB reinfection conferred by a previous omicron infection with vaccination was lower and waned faster than protection against BA.4 or BA.5 reinfection, which is indicative of the greater immune evasiveness of the XBB sublineage. Although severe COVID-19 is uncommon, populations remain vulnerable to future reinfection waves from emerging SARS-CoV-2 variants despite high rates of vaccination and infection, as reflected by substantially higher reinfection rates during Singapore's XBB wave than during the previous BA.5-driven wave. Policy makers could consider emerging public health interventions, such as omicron-adapted bivalent vaccines, to maintain population immunity against COVID-19. FUNDING: None.

Vaccine effectiveness against Delta, Omicron BA.1, and BA.2 in a highly vaccinated Asian setting: a test-negative design study.

OBJECTIVES: We compared the vaccine effectiveness over time of the primary series and booster against infection and severe disease with the Delta, Omicron BA.1, and BA.2 variants in Singapore, an Asian setting with high vaccination coverage. METHODS: We conducted a test-negative case-control study on all adult residents in Singapore who underwent PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in acute hospitals. Individuals with a negative PCR from 1 September, 2021, to 30 November, 2021, and 1 December, 2021, to 25 April, 2022, served as controls for the Delta and Omicron variants respectively, and PCR-positive individuals within these two time periods served as cases. Associations between vaccination status and severe SARS-CoV-2 infection and severe disease with the Delta or Omicron variants were measured using Poisson regressions. Vaccine effectiveness was calculated by taking 1 minus risk ratio. RESULTS: There were 68 114 individuals comprising 58 495 controls and 9619 cases for the Delta period, of whom 53 093 completed the primary series and 9161 were boosted. For the Omicron period, 104 601 individuals comprising 80 428 controls, 8643 BA.1 cases, and 15 530 BA.2 cases were included, of whom 29 183 and 71 513 were vaccinated with the primary series and boosted, respectively. The primary series provided greater protection against infection with Delta (45%, 95% CI 40-50%) than against infection with Omicron (21%, 95% CI 7-34% for BA.1; 18%, 95% CI 6-29% for BA.2) at <2 months from vaccination. Vaccine effectiveness of the booster was similar against infection with BA.1 (44%, 95% CI 38-50%) and BA.2 (40%, 95% CI 35-40%). Protection against severe disease by the booster for BA.1 (83%, 95% CI 76-88%) and BA.2 (78%, 95% CI 73-82%) was comparable to that by the primary series for Delta (80%, 95% CI 73-85%). CONCLUSION: Our findings support the use of a booster dose to reduce the risk of severe disease and mitigate the impact on the healthcare system in an Omicron-predominant epidemic.

Effectiveness of primary series and booster vaccination against SARS-CoV-2 infection and hospitalisation among adolescents aged 12-17 years in Singapore: a national cohort study.

BACKGROUND: Singapore offered the BNT162b2 vaccine (tozinameran; Pfizer-BioNTech) to adolescents aged 12-17 years in May 18, 2021, and extended booster vaccines to this group in Jan 21, 2022. Literature on the effectiveness of primary series and booster vaccination among adolescents is scarce outside of Europe and North America. We aimed to determine primary series and booster vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adolescents in Singapore. METHODS: For this national cohort study, we assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12-17 years vaccinated with BNT162b2 in Singapore from Sept 1 to Dec 15, 2021, during the delta (B.1.617.2) variant wave, and from Jan 21 to April 28, 2022, during the omicron (B.1.1.529) variant wave. Data were collected from official databases maintained by the Ministry of Health of Singapore. Individuals were classified as partly vaccinated (those who had received one dose and those who had received the second dose no more than 7 days previously), fully vaccinated (8 days after receiving a second dose), or boosted (8 days after receiving a third dose) and compared with unvaccinated individuals. FINDINGS: 249 763 individuals aged 12-17 years were included in the study, contributing over 56·2 million person-days of observation. Compared with unvaccinated individuals, two vaccine doses achieved vaccine effectiveness of 66% (95% CI 63-69) against infection with the delta variant and 25% (21-29) against infection with the omicron variant, and 83% (74-89) against delta variant-associated hospitalisation and 75% (56-86) against omicron variant-associated hospitalisation. Booster vaccination with a third dose achieved vaccine effectiveness of 56% (53-58) against infection with the omicron variant and 94% (86-97) against omicron-associated hospitalisation, compared with unvaccinated adolescents. Vaccine effectiveness against infection for both variants after two doses waned over time, whereas vaccine effectiveness against hospitalisation for both variants remained stable; both were increased after three doses. INTERPRETATION: Among adolescents aged 12-17 years, vaccine effectiveness against confirmed SARS-CoV-2 infection after two doses of BNT162b2 decreased over time and increased after a third dose. Boosted adolescents were also the most protected from hospitalisation compared with fully vaccinated, partly vaccinated, and unvaccinated adolescents. Therefore, the booster dose of BNT162b2 can help to reduce the burden on the health-care system and individual morbidity during an omicron wave. FUNDING: None.

Effectiveness of primary series and booster vaccination against SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years in Singapore: a national cohort study

Background Singapore offered the BNT162b2 vaccine (tozinameran;Pfizer-BioNTech) to adolescents aged 12–17 years in May 18, 2021, and extended booster vaccines to this group in Jan 21, 2022. Literature on the effectiveness of primary series and booster vaccination among adolescents is scarce outside of Europe and North America. We aimed to determine primary series and booster vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adolescents in Singapore. Methods For this national cohort study, we assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years vaccinated with BNT162b2 in Singapore from Sept 1 to Dec 15, 2021, during the delta (B.1.617.2) variant wave, and from Jan 21 to April 28, 2022, during the omicron (B.1.1.529) variant wave. Data were collected from official databases maintained by the Ministry of Health of Singapore. Individuals were classified as partly vaccinated (those who had received one dose and those who had received the second dose no more than 7 days previously), fully vaccinated (8 days after receiving a second dose), or boosted (8 days after receiving a third dose) and compared with unvaccinated individuals. Findings 249 763 individuals aged 12–17 years were included in the study, contributing over 56·2 million person-days of observation. Compared with unvaccinated individuals, two vaccine doses achieved vaccine effectiveness of 66% (95% CI 63–69) against infection with the delta variant and 25% (21–29) against infection with the omicron variant, and 83% (74–89) against delta variant-associated hospitalisation and 75% (56–86) against omicron variant-associated hospitalisation. Booster vaccination with a third dose achieved vaccine effectiveness of 56% (53–58) against infection with the omicron variant and 94% (86–97) against omicron-associated hospitalisation, compared with unvaccinated adolescents. Vaccine effectiveness against infection for both variants after two doses waned over time, whereas vaccine effectiveness against hospitalisation for both variants remained stable;both were increased after three doses. Interpretation Among adolescents aged 12–17 years, vaccine effectiveness against confirmed SARS-CoV-2 infection after two doses of BNT162b2 decreased over time and increased after a third dose. Boosted adolescents were also the most protected from hospitalisation compared with fully vaccinated, partly vaccinated, and unvaccinated adolescents. Therefore, the booster dose of BNT162b2 can help to reduce the burden on the health-care system and individual morbidity during an omicron wave. Funding None.

Effectiveness of BNT162b2 Vaccine against Omicron in Children 5 to 11 Years of Age.

BACKGROUND: Since it was first identified in early November 2021, the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread quickly and replaced the B.1.617.2 (delta) variant as the dominant variant in many countries. Data on the real-world effectiveness of vaccines against the omicron variant in children are lacking. METHODS: In a study conducted from January 21, 2022, through April 8, 2022, when the omicron variant was spreading rapidly, we analyzed data on children in Singapore who were 5 to 11 years of age. We assessed the incidences of all reported SARS-CoV-2 infections (confirmed on polymerase-chain-reaction [PCR] assay, rapid antigen testing, or both), SARS-CoV-2 infections confirmed on PCR assay, and coronavirus disease 2019 (Covid-19)-related hospitalizations among unvaccinated, partially vaccinated (≥1 day after the first dose of vaccine and up to 6 days after the second dose), and fully vaccinated children (≥7 days after the second dose). Poisson regression was used to estimate vaccine effectiveness from the incidence rate ratio of outcomes. RESULTS: A total of 255,936 children were included in the analysis. Among unvaccinated children, the crude incidence rates of all reported SARS-CoV-2 infections, PCR-confirmed SARS-CoV-2 infections, and Covid-19-related hospitalizations were 3303.5, 473.8, and 30.0 per 1 million person-days, respectively. Among partially vaccinated children, vaccine effectiveness was 13.6% (95% confidence interval [CI], 11.7 to 15.5) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5 to 28.9) against PCR-confirmed SARS-CoV-2 infection, and 42.3% (95% CI, 24.9 to 55.7) against Covid-19-related hospitalization; in fully vaccinated children, vaccine effectiveness was 36.8% (95% CI, 35.3 to 38.2), 65.3% (95% CI, 62.0 to 68.3), and 82.7% (95% CI, 74.8 to 88.2), respectively. CONCLUSIONS: During a period when the omicron variant was predominant, BNT162b2 vaccination reduced the risks of SARS-CoV-2 infection and Covid-19-related hospitalization among children 5 to 11 years of age.

Comparative Effectiveness of mRNA and Inactivated Whole-Virus Vaccines Against Coronavirus Disease 2019 Infection and Severe Disease in Singapore.

Compared with individuals vaccinated with Pfizer-BioNTech/Comirnaty, recipients of Sinovac-CoronaVac and Sinopharm were 2.37 (95% CI, 2.29-2.46) and 1.62 (95% CI, 1.43-1.85) times more likely to be infected with coronavirus disease 19, respectively, while individuals vaccinated with Moderna were 0.42 (95% CI, 0.25-0.70) times less likely to develop severe disease.

Connecting clusters of COVID-19: an epidemiological and serological investigation.

BACKGROUND: Elucidation of the chain of disease transmission and identification of the source of coronavirus disease 2019 (COVID-19) infections are crucial for effective disease containment. We describe an epidemiological investigation that, with use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays, established links between three clusters of COVID-19. METHODS: In Singapore, active case-finding and contact tracing were undertaken for all COVID-19 cases. Diagnosis for acute disease was confirmed with RT-PCR testing. When epidemiological information suggested that people might have been nodes of disease transmission but had recovered from illness, SARS-CoV-2 IgG serology testing was used to establish past infection. FINDINGS: Three clusters of COVID-19, comprising 28 locally transmitted cases, were identified in Singapore; these clusters were from two churches (Church A and Church B) and a family gathering. The clusters in Church A and Church B were linked by an individual from Church A (A2), who transmitted SARS-CoV-2 infection to the primary case from Church B (F1) at a family gathering they both attended on Jan 25, 2020. All cases were confirmed by RT-PCR testing because they had active disease, except for A2, who at the time of testing had recovered from their illness and tested negative. This individual was eventually diagnosed with past infection by serological testing. ELISA assays showed an optical density of more than 1·4 for SARS-CoV-2 nucleoprotein and receptor binding domain antigens in titres up to 1/400, and viral neutralisation was noted in titres up to 1/320. INTERPRETATION: Development and application of a serological assay has helped to establish connections between COVID-19 clusters in Singapore. Serological testing can have a crucial role in identifying convalescent cases or people with milder disease who might have been missed by other surveillance methods. FUNDING: National Research Foundation (Singapore), National Natural Science Foundation (China), and National Medical Research Council (Singapore).