Assessing COVID-19 vaccine effectiveness against Omicron subvariants: Report from a meeting of the World Health Organization.

Emerging in November 2021, the SARS-CoV-2 Omicron variant of concern exhibited marked immune evasion resulting in reduced vaccine effectiveness against SARS-CoV-2 infection and symptomatic disease. Most vaccine effectiveness data on Omicron are derived from the first Omicron subvariant, BA.1, which caused large waves of infection in many parts of the world within a short period of time. BA.1, however, was replaced by BA.2 within months, and later by BA.4 and BA.5 (BA.4/5). These later Omicron subvariants exhibited additional mutations in the spike protein of the virus, leading to speculation that they might result in even lower vaccine effectiveness. To address this question, the World Health Organization hosted a virtual meeting on December 6, 2022, to review available evidence for vaccine effectiveness against the major Omicron subvariants up to that date. Data were presented from South Africa, the United Kingdom, the United States, and Canada, as well as the results of a review and meta-regression of studies that evaluated the duration of the vaccine effectiveness for multiple Omicron subvariants. Despite heterogeneity of results and wide confidence intervals in some studies, the majority of studies showed vaccine effectiveness tended to be lower against BA.2 and especially against BA.4/5, compared to BA.1, with perhaps faster waning against severe disease caused by BA.4/5 after a booster dose. The interpretation of these results was discussed and both immunological factors (i.e., more immune escape with BA.4/5) and methodological issues (e.g., biases related to differences in the timing of subvariant circulation) were possible explanations for the findings. COVID-19 vaccines still provide some protection against infection and symptomatic disease from all Omicron subvariants for at least several months, with greater and more durable protection against severe disease.

Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression.

BACKGROUND: The global surge in the omicron (B.1.1.529) variant has resulted in many individuals with hybrid immunity (immunity developed through a combination of SARS-CoV-2 infection and vaccination). We aimed to systematically review the magnitude and duration of the protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against infection and severe disease caused by the omicron variant. METHODS: For this systematic review and meta-regression, we searched for cohort, cross-sectional, and case-control studies in MEDLINE, Embase, Web of Science, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, the WHO COVID-19 database, and Europe PubMed Central from Jan 1, 2020, to June 1, 2022, using keywords related to SARS-CoV-2, reinfection, protective effectiveness, previous infection, presence of antibodies, and hybrid immunity. The main outcomes were the protective effectiveness against reinfection and against hospital admission or severe disease of hybrid immunity, hybrid immunity relative to previous infection alone, hybrid immunity relative to previous vaccination alone, and hybrid immunity relative to hybrid immunity with fewer vaccine doses. Risk of bias was assessed with the Risk of Bias In Non-Randomized Studies of Interventions Tool. We used log-odds random-effects meta-regression to estimate the magnitude of protection at 1-month intervals. This study was registered with PROSPERO (CRD42022318605). FINDINGS: 11 studies reporting the protective effectiveness of previous SARS-CoV-2 infection and 15 studies reporting the protective effectiveness of hybrid immunity were included. For previous infection, there were 97 estimates (27 with a moderate risk of bias and 70 with a serious risk of bias). The effectiveness of previous infection against hospital admission or severe disease was 74·6% (95% CI 63·1-83·5) at 12 months. The effectiveness of previous infection against reinfection waned to 24·7% (95% CI 16·4-35·5) at 12 months. For hybrid immunity, there were 153 estimates (78 with a moderate risk of bias and 75 with a serious risk of bias). The effectiveness of hybrid immunity against hospital admission or severe disease was 97·4% (95% CI 91·4-99·2) at 12 months with primary series vaccination and 95·3% (81·9-98·9) at 6 months with the first booster vaccination after the most recent infection or vaccination. Against reinfection, the effectiveness of hybrid immunity following primary series vaccination waned to 41·8% (95% CI 31·5-52·8) at 12 months, while the effectiveness of hybrid immunity following first booster vaccination waned to 46·5% (36·0-57·3) at 6 months. INTERPRETATION: All estimates of protection waned within months against reinfection but remained high and sustained for hospital admission or severe disease. Individuals with hybrid immunity had the highest magnitude and durability of protection, and as a result might be able to extend the period before booster vaccinations are needed compared to individuals who have never been infected. FUNDING: WHO COVID-19 Solidarity Response Fund and the Coalition for Epidemic Preparedness Innovations.

A Systematic Review of Coronavirus Disease 2019 Vaccine Efficacy and Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Disease.

Billions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered globally, dramatically reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence and severity in some settings. Many studies suggest vaccines provide a high degree of protection against infection and disease, but precise estimates vary and studies differ in design, outcomes measured, dosing regime, location, and circulating virus strains. In this study, we conduct a systematic review of COVID-19 vaccines through February 2022. We included efficacy data from Phase 3 clinical trials for 15 vaccines undergoing World Health Organization Emergency Use Listing evaluation and real-world effectiveness for 8 vaccines with observational studies meeting inclusion criteria. Vaccine metrics collected include protection against asymptomatic infection, any infection, symptomatic COVID-19, and severe outcomes including hospitalization and death, for partial or complete vaccination, and against variants of concern Alpha, Beta, Gamma, Delta, and Omicron. We additionally review the epidemiological principles behind the design and interpretation of vaccine efficacy and effectiveness studies, including important sources of heterogeneity.

Assessing vaccine effectiveness against severe COVID-19 disease caused by omicron variant. Report from a meeting of the World Health Organization.

Vaccine effectiveness is lower and wanes faster against infection and symptomatic disease caused by the omicron variant of SARS-CoV-2 than was observed with previous variants. Vaccine effectiveness against severe omicron disease, on average, is higher, but has shown variability, including rapid apparent waning, in some studies. Assessing vaccine effectiveness against omicron severe disease using hospital admission as a measure of severe disease has become more challenging because of omicron's attenuated intrinsic severity and its high prevalence of infection. Many hospital admissions likely occur among people with incidental omicron infection or among those with infection-induced exacerbation of chronic medical conditions. To address this challenge, the World Health Organization held a virtual meeting on March 15, 2022, to review evidence from several studies that assessed Covid-19 vaccine effectiveness against severe omicron disease using several outcome definitions. Data was shown from studies in South Africa, the United States, the United Kingdom and Qatar. Several approaches were proposed that better characterize vaccine protection against severe Covid-19 disease caused by the omicron variant than using hospitalization of omicron-infected persons to define severe disease. Using more specific definitions for severe respiratory Covid-19 disease, such as indicators of respiratory distress (e.g. oxygen requirement, mechanical ventilation, and ICU admission), showed higher vaccine effectiveness than against hospital admission. Second, vaccine effectiveness against progression from omicron infection to hospitalization, or severe disease, also showed higher vaccine protection. These approaches might better characterize vaccine performance against severe Covid-19 disease caused by omicron, as well as future variants that evade humoral immunity, than using hospitalization with omicron infection as an indicator of severe disease.

Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression.

BACKGROUND: Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination. METHODS: This study was designed as a systematic review and meta-regression. We did a systematic review of preprint and peer-reviewed published article databases from June 17, 2021, to Dec 2, 2021. Randomised controlled trials of COVID-19 vaccine efficacy and observational studies of COVID-19 vaccine effectiveness were eligible. Studies with vaccine efficacy or effectiveness estimates at discrete time intervals of people who had received full vaccination and that met predefined screening criteria underwent full-text review. We used random-effects meta-regression to estimate the average change in vaccine efficacy or effectiveness 1-6 months after full vaccination. FINDINGS: Of 13 744 studies screened, 310 underwent full-text review, and 18 studies were included (all studies were carried out before the omicron variant began to circulate widely). Risk of bias, established using the risk of bias 2 tool for randomised controlled trials or the risk of bias in non-randomised studies of interventions tool was low for three studies, moderate for eight studies, and serious for seven studies. We included 78 vaccine-specific vaccine efficacy or effectiveness evaluations (Pfizer-BioNTech-Comirnaty, n=38; Moderna-mRNA-1273, n=23; Janssen-Ad26.COV2.S, n=9; and AstraZeneca-Vaxzevria, n=8). On average, vaccine efficacy or effectiveness against SARS-CoV-2 infection decreased from 1 month to 6 months after full vaccination by 21·0 percentage points (95% CI 13·9-29·8) among people of all ages and 20·7 percentage points (10·2-36·6) among older people (as defined by each study, who were at least 50 years old). For symptomatic COVID-19 disease, vaccine efficacy or effectiveness decreased by 24·9 percentage points (95% CI 13·4-41·6) in people of all ages and 32·0 percentage points (11·0-69·0) in older people. For severe COVID-19 disease, vaccine efficacy or effectiveness decreased by 10·0 percentage points (95% CI 6·1-15·4) in people of all ages and 9·5 percentage points (5·7-14·6) in older people. Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time. INTERPRETATION: COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20-30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy. FUNDING: Coalition for Epidemic Preparedness Innovations.

A global comprehensive vaccine-preventable disease surveillance strategy for the immunization Agenda 2030.

As part of the Immunization Agenda 2030, a global strategy for comprehensive vaccine-preventable disease (VPD) surveillance was developed. The strategy provides guidance on the establishment of high-quality surveillance systems that are 1) comprehensive, encompassing all VPD threats faced by a country, in all geographic areas and populations, using all laboratory and other methodologies required for timely and reliable disease detection; 2) integrated, wherever possible, taking advantage of shared infrastructure for specific components of surveillance such as data management and laboratory systems; 3) inclusive of all relevant data needed to guide immunization program management actions. Such surveillance systems should generate data useful to strengthen national immunization programs, inform vaccine introduction decision-making, and reinforce timely and effective detection and response. All stakeholders in countries and globally should work to achieve this vision.

Vaccine preventable diseases surveillance in Nepal: How much does it cost?

Assessing the cost of vaccine preventable diseases (VPD) surveillance is becoming more important in the context of the Global Polio Eradication Initiative (GPEI) funding transition, since GPEI support to polio surveillance helped the incremental building of VPD surveillance systems in many countries, including low income countries such as Nepal. However, there is limited knowledge on the cost of conducting VPD surveillance, especially the national cost for surveillance of multiple vaccine-preventable diseases. The current study sought to calculate the economic and financial costs of Nepal's comprehensive VPD surveillance systems from July 2016 to July 2017. At thecentral level, all surveillance units were included in the sample. At sub-national level, a purposive sampling strategy was used to select a representative sample from locations involved in conducting surveillance. The sub-national sample costs were extrapolated to the nationwide VPD surveillance system. Nepal's total annual economic cost of VPD surveillance was USD 4.81 million or USD 0.18 per capita, while the total financial cost was USD 4.38 million or USD 0.16 per capita. Government expenditures accounted for 56% of the total economic cost, and World Health Organization accounting for 44%. The biggest cost driver was personnel accounting for 51% of the total economic cost. WHO supported trained surveillance personnel through donor funding, mainly from Global Polio Eradication Initiative. As a polio transition priority country, Nepal will need to make strategic choices to fully self-finance or seek full donor support or a mixed-financing model as polio program funding diminishes.

Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.

Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2019.

In 2010, the World Health Assembly (WHA) set the following three milestones for measles control to be achieved by 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) among children aged 1 year to ≥90% at the national level and to ≥80% in every district, 2) reduce global annual measles incidence to <5 cases per 1 million population, and 3) reduce global measles mortality by 95% from the 2000 estimate* (1). In 2012, WHA endorsed the Global Vaccine Action Plan,† with the objective of eliminating measles§ in five of the six World Health Organization (WHO) regions by 2020. This report describes progress toward WHA milestones and regional measles elimination during 2000-2019 and updates a previous report (2). During 2000-2010, estimated MCV1 coverage increased globally from 72% to 84% but has since plateaued at 84%-85%. All countries conducted measles surveillance; however, approximately half did not achieve the sensitivity indicator target of two or more discarded measles and rubella cases per 100,000 population. Annual reported measles incidence decreased 88%, from 145 to 18 cases per 1 million population during 2000-2016; the lowest incidence occurred in 2016, but by 2019 incidence had risen to 120 cases per 1 million population. During 2000-2019, the annual number of estimated measles deaths decreased 62%, from 539,000 to 207,500; an estimated 25.5 million measles deaths were averted. To drive progress toward the regional measles elimination targets, additional strategies are needed to help countries reach all children with 2 doses of measles-containing vaccine, identify and close immunity gaps, and improve surveillance.

The epidemiology of rubella, 2007-18: an ecological analysis of surveillance data.

BACKGROUND: As of 2018, the rubella vaccine had been incorporated into the national immunisation schedule of 168 countries, representing 87% of the world's population. Countries have used different strategies to reduce the burden of congenital rubella syndrome (CRS), such as vaccinating only females. Given the different strategies, and that 26 countries still had not introduced the vaccine, we analysed global rubella surveillance data to understand rubella epidemiology and the effect of vaccination. METHODS: In this ecological analysis, we evaluated surveillance data on rubella cases that had been reported to WHO from 2007 to 2018, by age, vaccination history, and onset year. Cases were classified as either being vaccine eligible or ineligible on the basis of the country's vaccination strategy and the birth year of the person. We required all cases be confirmed by laboratory testing or that they were epidemiologically linked, and we excluded cases defined only by clinical symptoms. Incidence per million people was calculated by use of World Population Prospects data. FINDINGS: Between Jan 1, 2007, and Dec 31, 2018, from data reported to WHO as of Jan 3, 2020, there were 139 486 reported rubella cases, of which 15 613 (11%) were vaccine eligible. Annual incidence ranged from 13·9 cases per million in 2007 to 1·7 cases per million in 2018. In all years, absolute and proportional global incidence were higher among vaccine ineligible cohorts than eligible cohorts. In vaccine ineligible cohorts, 87 666 (74%) of 118 308 cases were in children younger than 15 years, compared with 8423 (54%) of 15 613 cases in vaccine eligible cohorts. Vaccine ineligible women of reproductive age (WRA) had a higher incidence than vaccine eligible WRA, except in 2011-12. INTERPRETATION: Vaccination has been successful in decreasing the burden of rubella, regardless of the strategy used. WRA remain at risk, but the risk is higher in those countries that have yet to introduce the vaccine. These countries should introduce the rubella-containing vaccine as soon as possible, to eliminate rubella, and to prevent the morbidity and mortality associated with CRS. FUNDING: None.

Measles and rubella IgG seroprevalence in persons 6 month-35 years of age, Mongolia, 2016.

BACKGROUND: In 2015-2016, Mongolia experienced an unexpected large measles outbreak affecting mostly young children and adults. After two nationwide vaccination campaigns, measles transmission declined. To determine if there were any remaining immunity gaps to measles or rubella in the population, a nationally representative serosurvey for measles and rubella antibodies was conducted after the outbreak was over. METHODS: A nationwide, cross-sectional, stratified, three-stage cluster serosurvey was conducted in November-December 2016. A priori, four regional strata (Ulaanbaatar, Western, Central, and Gobi-Eastern) and five age strata (6 months-23 months, 2-7 years, 8-17 years, 18-30 years, and 31-35 years) were created. Households were visited, members interviewed, and blood specimens were collected from age-appropriate members. Blood specimens were tested for measles immunoglobulin G (IgG) and rubella IgG (Enzygnost® Anti-measles Virus/IgG and Anti-rubella Virus/IgG, Siemens, Healthcare Diagnostics Products, GmbH Marburg, Germany). Factors associated with seropositivity were evaluated. RESULTS: Among 4598 persons aged 6 months to 35 years participating in the serosurvey, 94% were measles IgG positive and 95% were rubella IgG positive. Measles IgG seropositivity was associated with increasing age and higher education. Rubella IgG seropositivity was associated with increasing age, higher education, smaller household size, receipt of MMR in routine immunization, residence outside the Western Region, non-Muslim religious affiliation, and non-Kazakh ethnicity. Muslim Kazakhs living in Western Region had the lowest rubella seroprevalence of all survey participants. CONCLUSIONS: Nationally, high immunity to both measles and rubella has been achieved among persons 1-35 years of age, which should be sufficient to eliminate both measles and rubella if future birth cohorts have ≥ 95% two dose vaccination coverage. Catch-up vaccination is needed to close immunity gaps found among some subpopulations, particularly Muslim Kazakhs living in Western Region.

The Changing Global Epidemiology of Measles, 2013-2018.

BACKGROUND: Measles incidence and mortality rates have significantly decreased since vaccine introduction. Despite this progress, however, there has been a global resurgence of measles. To understand the current global epidemiology, we analyzed measles surveillance data. METHODS: We analyzed data on measles cases from 2013-2018 reported to the World Health Organization. Univariate analysis was undertaken based on age, vaccination history, onset year, World Health Organization region, and World Bank income status for the country where the case was reported, and a surrogate indicator of the historical strength of the country's immunization program. Annual incidence and a 2013-2018 mean country incidence per million were calculated. RESULTS: From 2013 through 2018, there were 899 800 reported measles cases, of which 57% occurred unvaccinated or undervaccinated persons, with an unknown vaccination history in another 30%. Lower-middle-income countries accounted for 66% of cases, 23% occurred in persons ≥15 years of age. In countries with stronger historical vaccination programs and higher country income, case patients had higher median ages. CONCLUSIONS: Although most measles case patients are <15 years of age, an age shift is seen in countries with a higher income or a stronger historical vaccination program. Countries must strengthen immunization programs to achieve high vaccination coverage; some must undertake strategies to reach persons ≥15 years of age and close immunity gaps.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2018.

In 2010, the World Health Assembly (WHA) set the following three milestones for measles control to be achieved by 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) among children aged 1 year to ≥90% at the national level and to ≥80% in every district, 2) reduce global annual measles incidence to less than five cases per 1 million population, and 3) reduce global measles mortality by 95% from the 2000 estimate* (1). In 2012, WHA endorsed the Global Vaccine Action Plan,† with the objective of eliminating measles§ in five of the six World Health Organization (WHO) regions by 2020. This report updates a previous report (2) and describes progress toward WHA milestones and regional measles elimination during 2000-2018. During 2000-2018, estimated MCV1 coverage increased globally from 72% to 86%; annual reported measles incidence decreased 66%, from 145 to 49 cases per 1 million population; and annual estimated measles deaths decreased 73%, from 535,600 to 142,300. During 2000-2018, measles vaccination averted an estimated 23.2 million deaths. However, the number of measles cases in 2018 increased 167% globally compared with 2016, and estimated global measles mortality has increased since 2017. To continue progress toward the regional measles elimination targets, resource commitments are needed to strengthen routine immunization systems, close historical immunity gaps, and improve surveillance. To achieve measles elimination, all communities and countries need coordinated efforts aiming to reach ≥95% coverage with 2 doses of measles vaccine (3).

Measles and rubella immunity in the population of Bhutan, 2017.

BACKGROUND: In 2017, measles elimination was verified in Bhutan, and the country appears to have sufficiently high vaccination coverage to achieve rubella elimination. However, a measles and rubella serosurvey was conducted to find if any hidden immunity gaps existed that could threaten Bhutan's elimination status. METHODS: A nationwide, three-stage, cluster seroprevalence survey was conducted among individuals aged 1-4, 5-17, and >20 years in 2017. Demographic information and children's vaccination history were collected, and a blood specimen was drawn. Serum was tested for measles and rubella immunoglobulin G (IgG). Frequencies, weighted proportions, and prevalence ratios for measles and rubella seropositivity were calculated by demographic and vaccination history, taking into account the study design. RESULTS: Of the 1325 individuals tested, 1045 (81%, 95% CI 78%-85%) were measles IgG seropositive, and 1290 (97%, 95% CI 95%-99%) were rubella IgG seropositive. Rubella IgG seropositivity was high in all three age strata, but only 47% of those aged 5-17 years were measles IgG seropositive. Additionally, only 41% of those aged 5-17 years who had documented receipt of two doses of measles- or measles-rubella-containing vaccine were seropositive for measles IgG, but almost all these children were rubella IgG seropositive. CONCLUSIONS: An unexpected measles immunity gap was identified among children 5-17 years of age. It is unclear why this immunity gap exists; however, it could have led to a large outbreak and threatened sustaining of measles elimination in Bhutan. Based on this finding, a mass vaccination campaign was conducted to close the immunity gap.

Selective Hepatitis B Birth-Dose Vaccination in São Tomé and Príncipe: A Program Assessment and Cost-Effectiveness Study.

São Tomé and Príncipe (STP) uses a selective hepatitis B birth-dose vaccination (HepB-BD) strategy targeting infants born to mothers who test positive for hepatitis B virus (HBV) surface antigen. We conducted a field assessment and economic analysis of the HepB-BD strategy to provide evidence to guide development of cost-effective policies to prevent perinatal HBV transmission in STP. We interviewed national stakeholders and key informants to understand policies, knowledge, and practices related to HepB-BD, vaccine management, and data recording/reporting. Cost-effectiveness of the existing strategy was compared with an alternate approach of universal HepB-BD to all newborns using a decision analytic model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2015 USD per HBV-associated death and per chronic HBV case prevented, from the STP health-care system perspective. We found that STP lacked national or facility-specific written policies and procedures related to HepB-BD. Timely HepB-BD to eligible newborns was considered a high priority, although timeliness of HepB-BD was not monitored. Compared with the existing selective vaccination strategy, universal HepB-BD would result in a 19% decrease in chronic HBV infections per year at overall cost savings of approximately 44% (savings of USD 5,441 each year). We estimate an ICER of USD 5,012 saved per HBV-associated death averted. The existing selective HepB-BD strategy in STP could be improved through documentation of policies, procedures, and timeliness of HepB-BD. Expansion to universal newborn HepB-BD without maternal screening is feasible and could result in cost savings if actual implementation costs and effectiveness fall within the ranges modeled.

Increase in Infant Measles Deaths During a Nationwide Measles Outbreak-Mongolia, 2015-2016.

BACKGROUND: Surveillance data from a large measles outbreak in Mongolia suggested increased case fatality ratio (CFR) in the second of 2 waves. To confirm the increase in CFR and identify risk factors for measles death, we enhanced mortality ascertainment and conducted a case-control study among infants hospitalized for measles. METHODS: We linked national vital records with surveillance data of clinically or laboratory-confirmed infant (aged <12 months) measles cases with rash onset during March-September 2015 (wave 1) and October 2015-June 2016 (wave 2). We abstracted medical charts of 95 fatal cases and 273 nonfatal cases hospitalized for measles, matched by age and sex. We calculated adjusted matched odds ratios (amORs) and 95% confidence intervals (CIs) for risk factors. RESULTS: Infant measles deaths increased from 3 among 2224 cases (CFR: 0.13%) in wave 1 to 113 among 4884 cases (CFR: 2.31%) in wave 2 (P < .001). Inpatient admission, 7-21 days before measles rash onset, for pneumonia or influenza (amOR: 4.5; CI, 2.6-8.0), but not other diagnoses, was significantly associated with death. DISCUSSION: Measles infection among children hospitalized with respiratory infections likely increased deaths due to measles during wave 2. Preventing measles virus nosocomial transmission likely decreases measles mortality.