[The Lancet Global Health, January 2023]

Background: The WHO Strategic Advisory Group of Experts recommended that an extended interval of 3–5 years between the two doses of the human papillomavirus (HPV) vaccine could be considered to alleviate vaccine supply shortages. However, three concerns have limited the introduction of extended schedules: girls could be infected between the two doses, the vaccination coverage for the second dose could be lower at ages 13–14 years than at ages 9–10 years, and identifying girls vaccinated with a first dose to give them the second dose could be difficult. Using mathematical modelling, we examined the potential effect of these concerns on the population-level impact and efficiency of extended dose HPV vaccination schedules.

Methods: We used HPV-ADVISE, an individual-based, transmission-dynamic model of multitype HPV infection and disease, calibrated to country-specific data for four low-income and middle-income countries (India, Viet Nam, Uganda, and Nigeria). For the extended dose scenarios, we varied the vaccination coverage of the second dose among girls previously vaccinated, the one-dose vaccine efficacy, and the one-dose vaccine duration of protection. We also examined a strategy in which girls aged 14 years were vaccinated irrespective of their previous vaccination status. We used a scenario of girls-only two-dose vaccination at age 9 years (vaccine=9 valent, vaccine-type efficacy=100%, duration of protection=lifetime, and coverage=80%) as our comparator. We estimated two outcomes: the relative reduction in the age-standardised cervical cancer incidence (population-level impact) and the number of cervical cancers averted per 100 000 doses (efficiency).

Findings: Our model projected substantial reductions in cervical cancer incidence over 100 years with the two-dose schedule (79–86% depending on the country), compared with no vaccination. Projections for the 5-year extended schedule, in which the second dose is given only to girls previously vaccinated at age 9 years, were similar to the current two-dose schedule, unless vaccination coverage of the second dose is very low (reductions in cervical cancer incidence of 71–78% assuming 30% coverage at age 14 years among girls vaccinated at age 9 years). However, when the dose at age 14 years is given to girls irrespective of vaccination status and assuming high vaccination coverage, the model projected a substantially greater reduction in cervical cancer incidence compared with the current two-dose schedule (reductions in cervical cancer incidence of 86–93% assuming 70% coverage at age 14 years, irrespective of vaccination status). Efficiency of the extended schedule was greater than the two-dose schedule, even with a drop in vaccination coverage.

Interpretation: The three concerns are unlikely to have a substantial effect on the population-level impact of extended dose schedules. Hence, extended dose schedules will likely provide similar cervical cancer reductions as two-dose schedules, while reducing the number of doses required in the short-term, providing a more efficient use of scarce resources, and offering a 5-year time window to reassess the necessity of the second dose.

Funding: WHO, Canadian Institute of Health Research Foundation, Fonds de recherche du Québec–Santé, Digital Research Alliance of Canada, and Bill & Melinda Gates Foundation.

[Clinical Infectious Diseases, December 2022]

Background: The Canadian coronavirus disease 2019 (COVID-19) immunization strategy deferred second doses and allowed mixed schedules. We compared 2-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in 2 of Canada’s larger provinces.

Methods: Two-dose VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or hospitalization among adults ≥18 years, including due to Alpha, Gamma, and Delta variants of concern (VOCs), was assessed ≥14 days postvaccination by test-negative design studies separately conducted in British Columbia and Quebec, Canada, between 30 May and 27 November (epi-weeks 22–47) 2021.

Results: In both provinces, all homologous or heterologous mRNA and/or ChAdOx1 2-dose schedules were associated with ≥90% reduction in SARS-CoV-2 hospitalization risk for ≥7 months. With slight decline from a peak of >90%, VE against infection was ≥80% for ≥6 months following homologous mRNA vaccination, lower by ∼10% when both doses were ChAdOx1 but comparably high following heterologous ChAdOx1 + mRNA receipt. Findings were similar by age group, sex, and VOC. VE was significantly higher with longer 7–8-week versus manufacturer-specified 3–4-week intervals between mRNA doses.

Conclusions: Two doses of any mRNA and/or ChAdOx1 combination gave substantial and sustained protection against SARS-CoV-2 hospitalization, spanning Delta-dominant circulation. ChAdOx1 VE against infection was improved by heterologous mRNA series completion. A 7–8-week interval between first and second doses improved mRNA VE and may be the optimal schedule outside periods of intense epidemic surge. Findings support interchangeability and extended intervals between SARS-CoV-2 vaccine doses, with potential global implications for low-coverage areas and, going forward, for children.

[JAMA Network Open, 14 October 2022]

Importance: The Omicron variant is phylogenetically and antigenically distinct from earlier SARS-CoV-2 variants and the original vaccine strain. Protection conferred by prior SARS-CoV-2 infection against Omicron reinfection, with and without vaccination, requires quantification.

Objective: To estimate the protection against Omicron reinfection and hospitalization conferred by prior heterologous non-Omicron SARS-CoV-2 infection and/or up to 3 doses of an ancestral, Wuhan-like messenger RNA (mRNA) vaccine.

Design, Setting, and Participants: This test-negative, population-based case-control study was conducted between December 26, 2021, and March 12, 2022, and included community-dwelling individuals aged 12 years or older who were tested for SARS-CoV-2 infection in the province of Quebec, Canada.

Exposures: Prior laboratory-confirmed SARS-CoV-2 infection with or without mRNA vaccination.

Main Outcomes and Measures: The main outcome was laboratory-confirmed SARS-CoV-2 reinfection and associated hospitalization, presumed to be associated with the Omicron variant according to genomic surveillance. The odds of prior infection with or without vaccination were compared for case participants with Omicron infection and associated hospitalizations vs test-negative control participants. Estimated protection was derived as 1 − the odds ratio, adjusted for age, sex, testing indication, and epidemiologic week. Analyses were stratified by severity and time since last non-Omicron infection or vaccine dose.

Results: This study included 696 439 individuals (224 007 case participants and 472 432 control participants); 62.2% and 63.9% were female and 87.4% and 75.5% were aged 18 to 69 years, respectively. Prior non-Omicron SARS-CoV-2 infection was detected for 9505 case participants (4.2%) and 29 712 control participants (6.3%). Among nonvaccinated individuals, prior non-Omicron infection was associated with a 44% reduction (95% CI, 38%-48%) in Omicron reinfection risk, which decreased from 66% (95% CI, 57%-73%) at 3 to 5 months to 35% (95% CI, 21%-47%) at 9 to 11 months postinfection and was below 30% thereafter. The more severe the prior infection, the greater the risk reduction. Estimated protection (95% CI) against Omicron infection was consistently significantly higher among vaccinated individuals with prior infection compared with vaccinated infection-naive individuals, with 65% (63%-67%) vs 20% (16%-24%) for 1 dose, 68% (67%-70%) vs 42% (41%-44%) for 2 doses, and 83% (81%-84%) vs 73% (72%-73%) for 3 doses. For individuals with prior infection, estimated protection (95% CI) against Omicron-associated hospitalization was 81% (66%-89%) and increased to 86% (77%-99%) with 1, 94% (91%-96%) with 2, and 97% (94%-99%) with 3 mRNA vaccine doses, without signs of waning.

Conclusions and Relevance: The findings of this study suggest that vaccination with 2 or 3 mRNA vaccine doses among individuals with prior heterologous SARS-CoV-2 infection provided the greatest protection against Omicron-associated hospitalization. In the context of program goals to prevent severe outcomes and preserve health care system capacity, a third mRNA vaccine dose may add limited protection in twice-vaccinated individuals with prior SARS-CoV-2 infection.

[The Lancet Infectious Diseases, 21 September 2022]

Background: There is a paucity of data on vaccine-induced or infection-induced (hybrid or natural) immunity against omicron (B.1.1.529) subvariant BA.2, particularly in comparing the effects of previous SARS-CoV-2 infection with the same or different genetic lineage. We aimed to estimate the protection against omicron BA.2 associated with previous primary infection with omicron BA.1 or pre-omicron SARS-CoV-2, among health-care workers with and without mRNA vaccination.

Methods: We conducted a test-negative case-control study among health-care workers aged 18 years or older who were tested for SARS-CoV-2 in Quebec, Canada, between March 27 and June 4, 2022, when BA.2 was the predominant variant and was presumptively diagnosed with a positive test result. We identified cases (positive test during study period) and controls (negative test during study period) using the provincial laboratory database that records all nucleic acid amplification testing for SARS-CoV-2 in Quebec, and used the provincial immunisation registry to determine vaccination status. Logistic regression models compared the likelihood of BA.2 infection or reinfection (second positive test ≥30 days after primary infection) among health-care workers who had previous primary infection and none to three mRNA vaccine doses versus unvaccinated health-care workers with no primary infection.

Findings: 258 007 SARS-CoV-2 tests were done during the study period. Among those with a valid result and that met the inclusion criteria, there were 37 732 presumed BA.2 cases (2521 [6·7%] reinfections following pre-omicron primary infection and 659 [1·7%] reinfections following BA.1 primary infection) and 73 507 controls (7360 [10·0%] had pre-omicron primary infection and 12 315 [16·8%] had BA.1 primary infection). Pre-omicron primary infection was associated with a 38% (95% CI 19–53) reduction in BA.2 infection risk, with higher BA.2 protection among those who had also received one (56%, 95% CI 47–63), two (69%, 64–73), or three (70%, 66–74) mRNA vaccine doses. Omicron BA.1 primary infection was associated with greater protection against BA.2 infection (risk reduction of 72%, 95% CI 65–78), and protection was increased further among those who had received two doses of mRNA vaccine (96%, 95–96), but was not improved with a third dose (96%, 95–97).

Interpretation: Health-care workers who had received two doses of mRNA vaccine and had previous BA.1 infection were subsequently well protected for a prolonged period against BA.2 reinfection, with a third vaccine dose conferring no improvement to that hybrid protection. If this protection also pertains to future variants, there might be limited benefit from additional vaccine doses for people with hybrid immunity, depending on timing and variant.

[Clinical Infectious Diseases, 1 July 2022]

Background: In Canada, first and second doses of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were uniquely spaced 16 weeks apart. We estimated 1- and 2-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Québec, Canada, including protection against varying outcome severity, variants of concern (VOCs), and the stability of single-dose protection up to 16 weeks postvaccination.

Methods: A test-negative design compared vaccination among SARS-CoV-2 test–positive and weekly matched (10:1), randomly sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by 1 dose ≥14 days or 2 doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression.

Results: Primary analysis included 5316 cases and 53 160 controls. Single-dose VE was 70% (95% confidence interval [CI], 68%–73%) against SARS-CoV-2 infection; 73% (95% CI, 71%–75%) against illness; and 97% (95% CI, 92%–99%) against hospitalization. Two-dose VE was 86% (95% CI, 81%–90%) and 93% (95% CI, 89%–95%), respectively, with no hospitalizations. VE was higher for non-VOCs than VOCs (73% Alpha) among single-dose recipients but not 2-dose recipients. Across 16 weeks, no decline in single-dose VE was observed, with appropriate stratification based upon prioritized vaccination determined by higher vs lower likelihood of direct patient contact.

Conclusions: One mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least 4 months postvaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy.

[Infectious Agents and Cancer, 8 November 2023]

Background: Understanding the role of naturally acquired (i.e., infection-induced) human papillomavirus (HPV) antibodies against reinfection is important given the high incidence of this sexually transmitted infection. However, the protective effect of naturally acquired antibodies in terms of the level of protection, duration, and differential effect by sex remains incompletely understood. We conducted a systematic review and a meta-analysis to (1) strengthen the evidence on the association between HPV antibodies acquired through past infection and subsequent type-specific HPV detection, (2) investigate the potential influence of type-specific HPV antibody levels, and (3) assess differential effects by HIV status.

Methods: We searched Embase and Medline databases to identify studies which prospectively assessed the risk of type-specific HPV detection by baseline homologous HPV serostatus among unvaccinated individuals. Random-effect models were used to pool the measures of association of naturally acquired HPV antibodies against subsequent incident detection and persistent HPV positivity. Sources of heterogeneity for each type were assessed through subgroup analyses stratified by sex, anatomical site of infection, male sexual orientation, age group, and length of follow-up period. Evidence of a dose-response relationship of the association between levels of baseline HPV antibodies and type-specific HPV detection was assessed. Finally, we pooled estimates from publications reporting associations between HPV serostatus and type-specific HPV detection by baseline HIV status.

Results: We identified 26 publications (16 independent studies, with 62,363 participants) reporting associations between baseline HPV serostatus and incident HPV detection, mainly for HPV-16 and HPV-18, the most detected HPV type. We found evidence of protective effects of baseline HPV seropositivity and subsequent detection of HPV DNA (0.70, 95% CI 0.61–0.80, NE = 11) and persistent HPV positivity (0.65, 95% CI 0.42–1.01, NE = 5) mainly for HPV-16 among females, but not among males, nor for HPV-18. Estimates from 8 studies suggested a negative dose–response relationship between HPV antibody level and subsequent detection among females. Finally, we did not observe any differential effect by baseline HIV status due to the limited number of studies available.

Conclusion: We did not find evidence that naturally acquired HPV antibodies protect against subsequent HPV positivity in males and provide only modest protection among females for HPV-16. One potential limitation to the interpretation of these findings is potential misclassification biases due to different causes.

[The Lancet Healthy Longevity, 14 July 2023]

Background: Older adults (aged ≥60 years) were prioritised for COVID-19 booster vaccination due to severe outcome risk, but the risk for this group is also affected by previous SARS-CoV-2 infection and vaccination. We estimated vaccine effectiveness against omicron-associated hospitalisation in older adults by previously documented infection, time since last immunological event, and age group.

Methods: This was a population-based test-negative case-control study done in Quebec, Canada, during BA.1 dominant (December, 2021, to March, 2022), BA.2 dominant (April to June, 2022), and BA.4/5 dominant (July to November, 2022) periods using provincial laboratory, immunisation, hospitalisation, and chronic disease surveillance databases. We included older adults (aged ≥60 years) with symptoms associated with COVID-19 who were tested for SARS-CoV-2 in acute-care hospitals. Cases were defined as patients who were hospitalised for COVID-19 within 14 days after testing positive; controls were patients who tested negative. Analyses spanned 3–14 months after last vaccine dose or previous infection. Logistic regression models compared COVID-19 hospitalisation risk by mRNA vaccine dose and previous infection versus unvaccinated and infection-naive participants.

Findings: Between Dec 26, 2021, and Nov 5, 2022, we included 174 819 specimens (82 870 [47·4%] from men and 91 949 [52·6%] from women; from 8455 cases and 166 364 controls), taken from 2951 cases and 48 724 controls in the BA.1 period; 1897 cases and 41 702 controls in the BA.2 period; and 3607 cases and 75 938 controls in the BA.4/5 period. In participants who were infection naive, vaccine effectiveness against hospitalisation improved with dose number, consistent with a shorter median time since last dose, but decreased with more recent omicron subvariants. Four-dose vaccine effectiveness was 96% (95% CI 93–98) during the BA.1 period, 84% (81–87) during the BA.2 period, and 68% (63–72) during the BA.4/5 period. Regardless of dose number (two to five doses) or timing since previous infection, hybrid protection was more than 90%, persisted for at least 6–8 months, and did not decline with age.

Interpretation: Older adults with both previous SARS-CoV-2 infection and two or more vaccine doses appear to be well protected for a prolonged period against hospitalisation due to omicron subvariants, including BA.4/5. Ensuring that older adults who are infection naive remain up to date with vaccination might reduce COVID-19 hospitalisations most efficiently.

[The Lancet Public Health, October 2023]

Background: Given the accumulating evidence that one-dose vaccination could provide high and sustained protection against human papillomavirus (HPV) infection and related diseases, we examined the population-level effectiveness and efficiency of one-dose HPV vaccination of girls compared with two-dose vaccination, using mathematical modelling.

Methods: In this mathematical modelling study, we used HPV-ADVISE LMIC, an individual-based transmission-dynamic model independently calibrated to four epidemiologically diverse low-income and middle-income countries (LMICs; India, Nigeria, Uganda, and Viet Nam). We parameterised and calibrated the model using sexual behaviour and epidemiological data identified from international population-based datasets and the literature. All base-case vaccination scenarios start in 2023 with the nonavalent vaccine and assumed 80% vaccination coverage with one or two doses. We assumed that two doses of vaccine provide 100% efficacy against vaccine-type infections and a lifelong duration of protection. We examined a non-inferior vaccination scenario for one dose compared with two doses, pessimistic scenarios of lower one-dose vaccine efficacy (85%) or a shorter duration of protection (ie, 20 or 30 years), and the effectiveness of a mitigation scenario in which schedules would switch from one dose to two doses. We also did sensitivity analyses by varying vaccination coverage. We used three outcomes: the relative reduction in cervical cancer incidence, the number of cervical cancers averted, and the number of vaccine doses needed to prevent one cervical cancer.

Findings: Assuming non-inferior vaccine characteristics for one dose compared with two doses, the model projections show that two-dose or one-dose routine vaccination of girls aged 9 years (with a multi-age cohort vaccination of girls aged 10–14 years) would avert 12·0 million (80% UI 9·5–14·5) cervical cancers in India, 4·7 million (3·4–5·8) in Nigeria, 2·3 million (1·9–2·6) in Uganda, and 0·4 million (0·2–0·5) in Viet Nam over 100 years. Under pessimistic assumptions of lower one-dose efficacy (85%) or a shorter duration of protection (ie, 30 years), one-dose routine vaccination would avert 69% (61–80) to 94% (92–96) of the cervical cancers averted with two-dose routine vaccination. However, when assuming a duration of protection of 20 years, one-dose routine vaccination would avert substantially fewer cervical cancers (ie, 35% [26–44] to 69% [65–71] of the cervical cancers averted with two-dose routine vaccination). A switch from one-dose to two-dose routine vaccination of girls aged 9 years, with a one-dose catch-up of girls aged 10–14 years, 5 years after the start of the vaccination programme, could mitigate potential losses in cervical cancer prevention from a short one-dose duration of protection (averting 92% [83–98] to 99% [97–100]) of the cervical cancers averted with two-dose routine vaccination). One-dose routine vaccination would result in fewer doses needed to prevent one cervical cancer than two-dose routine vaccination, even if the duration of protection is as low as 20 years. Finally, for countries with two-dose routine vaccination, adding one-dose multi-age cohort vaccination in the first year would provide similar benefits as a two-dose multi-age cohort vaccination, and would be more efficient even under the pessimistic assumptions of lower one-dose vaccine efficacy or duration of protection.

Interpretation: One-dose routine vaccination could avert most of the cervical cancers averted with two-dose vaccination while being more efficient, provided the duration of one-dose protection is greater than 20–30 years (depending on the LMIC). The doses saved by introducing one-dose routine vaccination could offer the opportunity to vaccinate girls before they age out of the vaccination window of 9–14 years and, potentially, to vaccinate boys or older age groups.