Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala

Clinical Infectious Diseases, Apr 2016

Background. Concerns remain about lower effectiveness and waning immunity of rotavirus vaccines in resource-poor populations. We assessed vaccine effectiveness against rotavirus in Guatemala, where both the monovalent (RV1; 2-dose series) and pentavalent (RV5; 3-dose series) vaccines were introduced in 2010. Methods. A case-control evaluation was conducted in 4 hospitals from January 2012 to August 2013. Vaccine status was compared between case patients (children with laboratory-confirmed rotavirus diarrhea) and 2 sets of controls: nondiarrhea “hospital” controls (matched by birth date and site) and nonrotavirus “test-negative” diarrhea controls (adjusted for age, birth month/year, and site). Vaccine effectiveness ([1 – odds ratio of vaccination] × 100%) was computed using logistic regression models. Results. We evaluated 213 case patients, 657 hospital controls, and 334 test-negative controls. Effectiveness of 2–3 doses of a rotavirus vaccine against rotavirus requiring emergency department visit or hospitalization was 74% (95% confidence interval [CI], 58%–84%) with hospital controls, and 52% (95% CI, 26%–69%) with test-negative controls. Using hospital controls, no significant difference in effectiveness was observed between infants 6–11 months (74% [95% CI, 18%–92%]) and children ≥12 months of age (71% [95% CI, 44%–85%]) (P = .85), nor between complete courses of RV1 (63% [95% CI, 23%–82%]) and RV5 (69% [95% CI, 29%–87%]) (P = .96). An uncommon G12P[8] strain, partially heterotypic to strains in both vaccines, was identified in 89% of cases. Conclusions. RV1 and RV5 were similarly effective against severe rotavirus diarrhea caused by a heterotypic strain in Guatemala. This supports broader implementation of rotavirus vaccination in low-income countries where >90% global deaths from rotavirus occur.

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Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala

CID Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala Paul A. Gastañaduy 1 2 3 Ingrid Contreras-Roldán 0 2 Chris Bernart 0 2 Beatriz López 0 2 Stephen R. Benoit 2 5 Marvin Xuya 0 2 Fredy Muñoz 0 2 Rishi Desai 1 2 3 Osbourne Quaye 1 2 4 Ka Ian Tam 1 2 Diana K. Evans-Bowen 1 2 Umesh D. Parashar 2 3 Manish Patel 2 3 John P. McCracken 0 2 0 Center for Health Studies, Universidad del Valle de Guatemala 1 National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia 2 tion and Respiratory Diseases, Centers for Disease Control and Prevention , 1600 Clifton Rd NE, MS A-34, Atlanta, GA 30333 3 Epidemic Intelligence Service 4 West African Center for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, University of Ghana , Legon 5 International Emerging Infections Program, Centers for Disease Control and Prevention , Guatemala City Background. Concerns remain about lower effectiveness and waning immunity of rotavirus vaccines in resource-poor populations. We assessed vaccine effectiveness against rotavirus in Guatemala, where both the monovalent (RV1; 2-dose series) and pentavalent (RV5; 3-dose series) vaccines were introduced in 2010. Methods. A case-control evaluation was conducted in 4 hospitals from January 2012 to August 2013. Vaccine status was compared between case patients (children with laboratory-confirmed rotavirus diarrhea) and 2 sets of controls: nondiarrhea “hospital” controls (matched by birth date and site) and nonrotavirus “test-negative” diarrhea controls (adjusted for age, birth month/year, and site). Vaccine effectiveness ([1 - odds ratio of vaccination] × 100%) was computed using logistic regression models. Results. We evaluated 213 case patients, 657 hospital controls, and 334 test-negative controls. Effectiveness of 2-3 doses of a rotavirus vaccine against rotavirus requiring emergency department visit or hospitalization was 74% (95% confidence interval [CI], 58%-84%) with hospital controls, and 52% (95% CI, 26%-69%) with test-negative controls. Using hospital controls, no significant difference in effectiveness was observed between infants 6-11 months (74% [95% CI, 18%-92%]) and children ≥12 months of age (71% [95% CI, 44%-85%]) (P = .85), nor between complete courses of RV1 (63% [95% CI, 23%-82%]) and RV5 (69% [95% CI, 29%87%]) (P = .96). An uncommon G12P[8] strain, partially heterotypic to strains in both vaccines, was identified in 89% of cases. Conclusions. RV1 and RV5 were similarly effective against severe rotavirus diarrhea caused by a heterotypic strain in Guatemala. This supports broader implementation of rotavirus vaccination in low-income countries where >90% global deaths from rotavirus occur. - To help control the large burden of childhood deaths and hospitalizations associated with rotavirus disease, the World Health Organization (WHO) recommends all infants receive 1 of 2 live oral rotavirus vaccines, a monovalent human vaccine (Rotarix [RV1], GlaxoSmithKline Biologicals, Rixensart, Belgium), or a pentavalent bovine-derived vaccine (RotaTeq [RV5], Merck and Co, Whitehouse Station, New Jersey) [ 1 ]. Although both vaccines were found to perform well in prelicensure studies in middle- and high-income countries, where efficacy ranged from 77% to 98% [ 2–4 ], the efficacy of these vaccines was lower (18%–64%) in low-income settings of Africa and Asia [ 5–7 ]. The lower efficacy in low-income populations may be related to host and environmental factors (eg, enteric coinfections, concurrent oral polio vaccine administration, micronutrient malnutrition, transplacental maternal antibodies, and human immunodeficiency virus infection) that could impede initial immune responses and adversely affect vaccine performance [ 8, 9 ]. Accordingly, evaluating vaccine effectiveness (VE) under routine conditions in resource-limited settings remains a public health priority. Although >25 middle- and high-income countries have adopted rotavirus vaccines for routine childhood immunization, and several of these countries have documented large declines in rotavirus disease burden, fewer low-income countries are currently using rotavirus vaccines [ 10 ]. As a result, there are limited data on the field performance of these vaccines in developing countries, and WHO has emphasized the need for additional VE data from these settings [ 1 ]. In addition, previous field assessments in low-income settings in Latin America [ 11, 12 ], as well as recent clinical trials in Africa and Asia [ 5, 7 ], have shown a decline in protection in children aged >1 year, suggesting waning immunity in resource-limited settings. Moreover, given the differences in strain makeup between RV1 and RV5, and the constant evolution of new strains in resource-poor settings [ 13, 14 ], measuring RV1 and RV5 effectiveness during contemporaneous use in the same population is important. In particular, no previous evaluations have assessed the performance of both vaccines during concurrent use in a lower middle-income setting. We conducted a case-control study to assess the effectiveness of both RV1 and RV5 during contemporaneous use against rotavirus diarrhea requiring emergency department (ED) care or hospitalization in Guatemala. METHODS Settings Guatemala is a lower middle-income country in Central America with a gross national income (GNI) per capita of $3070 annually and an annual birth cohort of approximately 298 154 live births (http://data.worldbank.org/). In February 2010, Guatemala’s Ministry of Health (Ministerio de Salud Publica de Guatemala [MSPAS]) introduced RV5 into its routine immunization program, with 3 doses recommended at ages 2, 4, and 6 months. In July 2010, the MSPAS began to vaccinate with RV1 instead of RV5, with 2 doses recommended at ages 2 and 4 months. From 1 January 2012 to 30 August 2013, we conducted active hospital-based diarrhea surveillance in the pediatric ED and wards of 4 national hospitals in Guatemala (2 urban hospitals in the capital, Guatemala City, and 1 rural hospital each in Cuilapa and Quetzaltenango). Participants: Case Patients and Controls A case patient was defined as a child visiting the ED and/or hospitalized for laboratory-confirmed rotavirus diarrhea and who was age-eligible to receive rotavirus vaccination (born after 1 June 2009). Vaccine effectiveness was assessed using 2 groups of controls: children hospitalized for a condition unrelated to diarrhea (ie, “hospital” controls), and children with rotavirusnegative diarrhea (ie, “test-negative” controls). After a case patient was identified, up to 3 hospital controls matched to the case patient’s date of birth (±30 days) were sequentially enrolled during the study period in the same hospital. Test-negative controls were those children who were enrolled during surveillance for diarrhea but that tested negative for rotavirus. Data Collection After written informed consent, parents or guardians of case patients and controls were interviewed face to face for information on demographics, socioeconomic factors, birth weight, history of breastfeeding, and the child’s medical history. For both case patients and test-negative controls, data on clinical characteristics, treatment, and the illness course were also collected from the medical record and the hospital staff providing care. Rotavirus vaccination status was confirmed by review of vaccination cards if available from the parents during enrollment (88%), or from logbooks at the clinic where the child was reportedly vaccinated (12%). Case patients and controls were considered vaccinated with the corresponding number of doses (eg, 1, 2, or 3) if the most recent dose was administered ≥14 days before the date of presentation. If available, the type of vaccine (RV1 or RV5) was abstracted from the vaccination card or clinic logbooks. Specimen Collection, Storage, and Laboratory Testing Bulk stool specimens were collected from children presenting with diarrhea within 48 hours of the hospital visit. In the 2 urban hospitals in Guatemala City, specimens were stored at 2°C–8°C prior to biweekly or weekly transfer to the Universidad del Valle de Guatemala, where testing for rotavirus antigen using a commercially available enzyme immunoassay (EIA) kit (ProSpecT Rotavirus Microplate Assay, Oxoid, United Kingdom) was performed. For Culiapa and Quetzaltenango, EIA rotavirus antigen testing was performed in-hospital. Specimens were stored frozen at −70°C and shipped to the Centers for Disease Control and Prevention (Atlanta, Georgia), where rotavirus-positive specimens were genotyped to determine the infecting strain, using methods previously described [ 15 ]. Sample Size and Data Analysis Using a precision-based approach, we estimated that a total of 170 case patients would be needed to compute a VE of 60% with confidence limit width of 30%, using a matched design with a hospital control-to-case ratio of 3:1 and vaccine coverage of 50%. The main objective of this study was to estimate the effectiveness of rotavirus vaccination against rotavirus-associated ED visit or hospitalization. Primary analyses assessed the effectiveness of a full series of RV1 (2 doses), a full series of RV5 (3 doses), or 2–3 doses of a rotavirus vaccine (either RV1, RV5, or unrecorded vaccine type), compared with no dose. To identify potential confounders or biases for the association between rotavirus vaccination and subsequent rotavirus diarrhea, we conducted bivariate analyses to assess for differences in characteristics and indicators of socioeconomic status between case patients and the 2 control groups. Differences in categorical data were assessed using χ2 tests; continuous variables were assessed with the Wilcoxon rank-sum test. We then compared the proportion vaccinated among case patients and controls. VE was calculated using only data from children with confirmed vaccination, ensuring use of accurately ascertained vaccination status. Two separate logistic regression models were constructed to calculate the odds ratios with 95% confidence intervals (CIs) of rotavirus vaccination in case patients vs each of the control groups. For hospital controls, conditional logistic regression models were used to account for matching by date of birth and site (hospital). For test-negative controls, unconditional logistic regression models that adjusted for age (in months), birth month/year, and hospital were used. Adjusting for time of birth and hospital in the base models is important because it controls for potential confounding due to variation in vaccination coverage from month to month and by geographic location. We also assessed for additional confounding by including in the model variables with a P value ≤.20 in the bivariate analyses. Hierarchical backward elimination approach was used to select the covariates in the final model, retaining variables significant at P < .05. Subgroup analyses were conducted using the same approach to assess (1) protection from receipt of 1 dose of a rotavirus vaccine; (2) protection from receipt of 1 or more doses of a rotavirus vaccine (intention-to-vaccinate analysis); (3) strainspecific protection (against the predominant rotavirus genotype); (4) duration of protection after vaccination, by measuring effectiveness among children 6–11 months of age compared to those aged ≥12 months (here an interaction term was included between age and vaccine receipt in the regression models); and (5) for a potential gradient in protection against illness of varying severity, using a previously described 20-point clinical severity score (Vesikari scale) [ 16 ]; illnesses with scores ≥11 were classified as severe and illnesses with scores ≥15 were classified as very severe. To assess for a difference in effectiveness between RV1 and RV5, regression models were repeated limiting analyses to case patients and controls who had received either RV1 or RV5 and including a term for vaccine type in the model. VE was calculated as (1 – odds ratio) × 100%. Statistical significance was designated as a P value <.05. Analyses were performed using SAS statistical software (version 9.3). RESULTS A total of 261 case patients, 769 hospital controls, and 387 testnegative controls were enrolled. Of the 261 case patients, 221 (85%) received intravenous rehydration, 111 (43%) were hospitalized for a median duration of 2 days, and 1 died. The age distribution of case patients was as follows: 33 (13%) were <6 months, 90 (34%) were 6–11 months, 116 (44%) were 12–23 months, and 22 (8%) were ≥24 months of age. Vaccine status was confirmed for 85% (1204/1417) of participants. There were no differences in demographic or socioeconomic variables among children with confirmed and nonconfirmed vaccination (P > .06 for all), except for the number of children in the home (2 [range, 1–40] vs 2 [range, 1–6], respectively; P = .008). No significant difference in confirmation of vaccination status was noted among case patients (82% [213/261]), hospital controls (85% [657/769]), or test-negative controls (86% [334/387]) (P = .23). Compared to hospital controls, case patients were more likely to be younger at presentation, more likely to be male, and less likely to have a chronic underlying illness (Table 1). Compared to test-negative controls, case patients were older and less likely to have a chronic underlying illness. Overall, among case patients, hospital controls, and testnegative controls, respectively, 39% (84/213), 22% (145/657), and 22% (73/334) were unvaccinated, and 61% (129/213), 78% (512/657), and 78% (261/334) received 1 dose or more. Among 709 children who received 2–3 doses, information on rotavirus vaccine type (RV1 or RV5) was available for 430 (61%), including 60 case patients, 253 hospital controls, and 117 testnegative controls; 71% (306/430) received RV1 and 29% (124/ 430) received RV5. Among children with information on vaccine type, no mixed series were identified, and <1% (1/430) of completed series were given incorrectly (on 1 occasion, 3 RV1 doses were administered). Doses of RV5 were administered between February 2010 and March 2013, whereas doses of RV1 were administered between July 2010 and May 2013. Effectiveness of 2–3 doses of a rotavirus vaccine against rotavirus diarrhea requiring an ED visit or hospitalization was 74% (95% CI, 58%–84%) in the analysis with hospital controls, and 52% (95% CI, 26%–69%) in the analysis with test-negative controls (Table 2). One dose of a rotavirus vaccine also provided significant protection of 59% (95% CI, 26%–78%) with hospital controls, and 60% (95% CI, 27%–78%) with test-negative controls. In the intention-to-vaccinate analysis, effectiveness of 1 or more doses was 64% (95% CI, 45%–77%) with hospital controls, and 55% (95% CI, 31%–71%) with test-negative controls. A complete 2-dose course of RV1 and a complete 3-dose course of RV5, respectively, were 63% (95% CI, 23%–82%) and 69% (95% CI, 29%–87%) effective using hospital controls, and 51% (95% CI, 15%–71%) and 43% (95% CI, −18% to 72%) effective using test-negative controls. We did not find a significant difference in effectiveness between the 2 types of vaccine using either hospital controls (P = .96) or test-negative controls (P = .61). Among 145 case patients with complete clinical information on rotavirus severity, 15 (10%) were classified as mild to moderate (Vesikari score ≤10), 90 (62%) as severe (Vesikari score ≥11 and <15), and 40 (28%) as very severe (Vesikari score ≥15). Protection was similar against the 2 levels of disease severity we evaluated. With hospital controls, 2–3 doses of a rotavirus vaccine provided protection of 73% (95% CI, 50%–86%) against rotavirus diarrhea with severity score ≥11 and 76% (95% CI, 18%–93%) against severity score ≥15 (Table 3). No significant differences in effectiveness of 2–3 doses of a rotavirus vaccine against a rotavirus ED visit or hospitalization were observed between children 6–11 months of age compared with children ≥12 months of age: 74% (95% CI, 18%–92%) vs 71% (95% CI, 44%–85%) using hospital controls (P = .85), and 73% (95% CI, 35%–89%) vs 53% (95% CI, 12%–75%) using test-negative controls (P = .76) (Table 3). Strain characterization was conducted for 99% (258/261) of rotavirus-positive specimens. Among these, G12P[ 8 ] was the predominant strain, detected in 89% (229/258) of the samples. G12P[ 8 ] is partially heterotypic to both vaccines (ie, the G component is not among the strains contained in the vaccines). G2P [ 4 ] was detected in 5% (14/258) of samples; the remaining 6% were sparsely detected strains (G3P[ 6 ], G3P[ 8 ], G9P[ 8 ]) and mixed infections. Two- or 3-dose VE specific against G12P[ 8 ] alone was 74% (95% CI, 55%–85%) with hospital controls, and 54% (95% CI, 28%–71%) with test-negative controls (Table 3). Effectiveness of RV1 and RV5 against rotavirus caused by G12P [ 8 ] was 62% (95% CI, 14%–83%) and 73% (95% CI, 24%–90%) using hospital controls, and 55% (95% CI, 21%–74%) and 39% (95% CI, −30% to 71%) using test-negative controls, respectively. DISCUSSION During routine programmatic use in a lower middle-income country, we demonstrate that 2–3 doses of a rotavirus vaccine was approximately 50%–70% effective against rotavirusassociated ED visits or hospitalizations. In the context of earlier postlicensure evaluations in Latin America, this estimate is what we would expect for Guatemala, based on the gradient of effectiveness by socioeconomic status of the population. A full series of RotaTeq provided 44% protection against severe rotavirus disease in Nicaragua (GNI $1866), and effectiveness of Rotarix was 69%–77% in Bolivia (GNI $2280), 76% in El Salvador (GNI $3730), and 85% in Brazil (GNI $12 160) [ 17 ]. The finding of similar effectiveness of RotaTeq and Rotarix in Guatemala supports the notion that differences in host and environmental factors are the likely cause of the heterogeneity in vaccine performance. Importantly, demonstration of a protective effect in this and other resource-limited settings is encouraging, as it is in these populations with high baseline rates of severe rotavirus outcomes where these vaccines offer their greatest life-saving potential. This is the first postlicensure assessment of the performance of both rotavirus vaccines during concurrent use in a developing country. Using hospital controls, we showed that 2 doses of RV1 and 3 doses of RV5 were similarly effective against rotavirus disease requiring an ED visit or hospitalization, with VE estimates of 63% (95% CI, 23%–82%) and 69% (95% CI, 29%–87%), respectively. Our evaluation was not powered to measure differences in effectiveness between the 2 vaccines and, thus, prudent interpretation is warranted. However, 3 previous field effectiveness evaluations in 2 high-income countries where concomitant use of both vaccines has been evaluated [ 18–20 ] also did not find any evidence of a difference in effectiveness between RV1 and RV5. Moreover, because almost 90% of strains were of the G12 genotype, we were able to estimate effectiveness for RV1 and RV5 against this emerging genotype (62% [95% CI, 14%–83%] and 73% [95% CI, 24%–90%], respectively). A previous study had demonstrated a protective effect against G12 strains for RV5 only, and in a high-income setting [ 19 ]. Our findings contribute to accumulating evidence showing that both vaccines appear to provide good protection against a wide range of homotypic and heterotypic rotavirus strains, as shown in both clinical trials and postlicensure evaluations [ 2–7, 11, 12, 21 ]. Our study provides evidence for considerable protection (approximately 60%) against severe rotavirus diarrhea from 1 dose of rotavirus vaccine among children in Guatemala. This shortperiod protection, before completion of a full schedule, is particularly reassuring for low-income countries, where a substantial proportion of rotavirus hospitalizations and deaths occurs among infants aged <6 months [ 22, 23 ], and where many infants may not return to complete their vaccination series. We also note sustained protection through the second year of life, the age period within which most rotavirus hospitalizations occur in developing countries [ 22, 24 ]. Conversely, a larger study in Nicaragua [ 12, 25 ], the poorest setting in which the field performance of RV5 has been evaluated, as well as clinical trials of both RV1 and RV5 in Africa [ 5, 26 ], have demonstrated an approximate 2- to 3-fold decline in protection after the first year of life. In addition, studies in poor populations in Brazil and Australia suggest that effectiveness against fully heterotypic strains may decline more rapidly than protective immunity against homotypic strains. Thus, it is in the most impoverished regions, where factors that impair initial immune responses to vaccines and strain diversity are more prominent, that waning immunity may become most apparent. This warrants additional monitoring of rotavirus disease incidence among older children, and consideration of other interventions in resource-limited settings [ 27 ]. A few limitations should be considered. We cannot be certain that our controls ideally represent the distribution of vaccination histories in the source population of case patients. Confounding bias was likely decreased by matching and adjustments for age and site, and the similarity in measures of socioeconomic status between case patients and controls was reassuring. Because not all families bring the child’s immunization card to the hospital in Guatemala, we were able to obtain vaccination records for only about 85% of participants, and children with unknown vaccination (no card or clinic logbook available) were excluded from the analyses. However, there were no differences in confirmation between case patients and controls, and characteristics and indicators of socioeconomic status did not differ significantly between children with confirmed and nonconfirmed vaccination, and so their respective rates of vaccination are expected to be similar. Finally, although significant estimates of RV1 and RV5 effectiveness were obtained with hospital controls, approximately 40% of case patients and controls who had received 2–3 doses lacked documentation of vaccine type, and thus our CIs were wide and nonsignificant for RV5 using test-negative controls. Neither subgroup analyses (duration of protection, partial vaccination, gradient by severity) for each of the vaccine types were possible due to a small sample size. In summary, rotavirus vaccination provided substantial protection against severe rotavirus diarrhea in a lower middleincome country setting in Latin America. We found good and similar protection from complete courses of both RV1 and RV5. Considerable protection was also conferred by 1 dose of vaccine, vaccine effect was sustained among children ≥1 year of age, and effectiveness was confirmed against a strain partially heterotypic to both vaccines. Our findings reinforce WHO recommendations for continued implementation of rotavirus vaccination in low-income countries, where >90% of the annual deaths from rotavirus occur. Notes Acknowledgments. We thank Cesar Racancoj, Aleida Roldan, Mathew Esona, Rashi Gautam, Slavica Mijatovic-Rustempasic, and Michael Bowen for their laboratory support, and Kimberly Pringle for help in ascertainment of vaccination status at immunization clinics. We also thank all the members of the research team in Guatemala involved in the enrollment of the participants for this evaluation, as well as the Guatemala Ministry of Health and the staff at participating hospitals for their cooperation. Disclaimer. This work was funded by the Centers for Disease Control and Prevention (CDC), Department of Health and Human Services, but the final document was submitted at the sole discretion of the authors. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. The views expressed by the authors do not necessarily reflect the views of PATH, the CDC Foundation, the Bill and Melinda Gates Foundation, or GAVI, the Vaccine Alliance. Financial support. This work was supported by the CDC (cooperative agreement number UO1 GH000028-02). Supplement sponsorship. This article appears as part of the supplement “Health Benefits of Rotavirus Vaccination in Developing Countries,” sponsored by PATH and the CDC Foundation through grants from the Bill and Melinda Gates Foundation and GAVI, the Vaccine Alliance. Potential conflicts of interests. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. D o w n l o a d e d f r o m h t t p : / / c i d . o x f o r d j o u r n a l s . o r g / b y g u e s t o n A p r i l 8 , 2 0 1 6 1. Rotavirus vaccines: an update . Wkly Epidemiol Rec 2009 ; 84 : 533 - 40 . 2. Linhares AC , Velazquez FR , Perez-Schael I , et al. 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Paul A. Gastañaduy, Ingrid Contreras-Roldán, Chris Bernart, Beatriz López, Stephen R. Benoit, Marvin Xuya, Fredy Muñoz, Rishi Desai, Osbourne Quaye, Ka Ian Tam, Diana K. Evans-Bowen, Umesh D. Parashar, Manish Patel, John P. McCracken. Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala, Clinical Infectious Diseases, 2016, S121-S126, DOI: 10.1093/cid/civ1208