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Retention in prevention of mother-to-child transmission (PMTCT) care is critical to prevent vertical HIV transmission and reduce morbidity and mortality of mother-infant pairs. We investigated whether weekly, interactive text-messaging improved 18-month postpartum retention in PMTCT care. This randomised, two-armed, parallel trial was conducted at six PMTCT clinics in western Kenya. Pregnant women with HIV at least 18 years of age with access to a mobile phone, able to text-message, or had somebody who could text on their behalf, were eligible. Participants were randomly assigned at a 1:1 ratio in block sizes of four to the intervention or control group. The intervention group received weekly text messages asking "How are you?" ("Mambo?" in Swahili) and were requested to respond within 48 h. Healthcare workers called women who indicated a problem or did not respond. The intervention was administered up to 24 months after delivery. Both groups received standard care. The primary outcome was retention in care at 18 months postpartum (i.e., clinic attendance 16–24 months after delivery based on data from patient files, patient registers and Kenya's National AIDS and STI Control Programme database), which was analysed by intention-to-treat. Researchers and data collectors were masked to group assignment, while healthcare workers were not. Between June 25th, 2015, and July 5th, 2016, we randomly assigned 299 women to the intervention and 301 to standard care only. Follow-up concluded on July 26th, 2019. The proportion of women retained in PMTCT care at 18 months postpartum was not significantly different between the intervention (n = 210/299) and control groups (n = 207/301) (risk ratio 1.02, 95% confidence interval 0.92–1.14, p = 0.697). No adverse events related to the mobile phone intervention were reported. Weekly, interactive text-messaging was not associated with improved retention in PMTCT care at 18 months postpartum or linkage to care up to 30 months postpartum in this setting. (ISRCTN No. 98818734). [ABSTRACT FROM AUTHOR]

Mother-to-child transmission of HIV remains a significant concern in Africa despite earlier progress. Early infant diagnosis (EID) of HIV is crucial to reduce mortality among infected infants through early treatment initiation. However, a large proportion of HIV-exposed infants are still not tested in Kenya. Our objective was to investigate whether weekly interactive text-messages improved prevention of mother-to-child transmission (PMTCT) of HIV care outcomes including EID HIV testing. This multicentre, parallel-group, randomised, open-label trial included six antenatal care clinics across western Kenya. Pregnant women living with HIV, aged 18 years or older, with mobile phone access, were randomised in a 1:1 ratio to weekly text messages that continued until 24 months postpartum, asking "How are you?" ("Mambo?") to which they were asked to respond within 48 h, or a control group. Healthcare workers contacted participants reporting problems and non-responders by phone. Participants in both groups received routine PMTCT care. The prespecified secondary outcome reported in this paper is EID HIV testing by eight weeks of age (blinded outcome assessment). Final 24-months trial results will be published separately. We estimated risk ratios using Poisson regression with robust standard errors. Between June 2015–July 2016, we screened 735 pregnant women, of whom 600 were enrolled: 299 were allocated to the intervention and 301 to the control group. By eight weeks of age, the uptake of EID HIV testing out of recorded live births was 85.5% in the intervention and 84.7% in the control group (71.2% vs. 71.8% of participants randomised, including miscarriages, stillbirths, etc.). The intention-to-treat risk ratio was 0.99; 95% CI: 0.90–1.10; p = 0.89. The proportion of infants diagnosed with HIV was 0.8% in the intervention and 1.2% in the control group. No adverse events were reported. We found no evidence to support that the WelTel intervention improved EID HIV testing. A higher uptake of EID testing than expected in both groups may be a result of lower barriers to EID testing and improved PMTCT care in western Kenya, including the broader standard use of mobile phone communication between healthcare workers and patients. (ISRCTN No. 98818734. Funded by the European-Developing Countries Clinical Trial Partnership and others). [ABSTRACT FROM AUTHOR]

An intermediate response measure that accurately predicts efficacy in a new setting at the individual level could be used both for prediction and personalized medical decisions. In this article, we define a predictive individual-level general surrogate (PIGS), which is an individual-level intermediate response that can be used to accurately predict individual efficacy in a new setting. While methods for evaluating trial-level general surrogates, which are predictors of trial-level efficacy, have been developed previously, few, if any, methods have been developed to evaluate individual-level general surrogates, and no methods have formalized the use of cross-validation to quantify the expected prediction error. Our proposed method uses existing methods of individual-level surrogate evaluation within a given clinical trial setting in combination with cross-validation over a set of clinical trials to evaluate surrogate quality and to estimate the absolute prediction error that is expected in a new trial setting when using a PIGS. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate individual-level general surrogates over a set of multi-national trials of a pentavalent rotavirus vaccine. [ABSTRACT FROM AUTHOR]

In the article, the authors present their analysis of the Danish randomized trial on the effects of proposed masking protocols (DANMASK-19) against the serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a causal inference perspective. Topics include the intent-to-treat effect in randomized experiments, how to avoid missing data in randomized experiments and the calculation of reported summary statistics.

Background: Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults.Methods: This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase. Healthy village residents aged 18-45 years were eligible if they had normal laboratory results (including HIV, hepatitis B, hepatitis C tests) and had not received a previous malaria vaccine or recent immunosuppressive drugs, vaccines, or blood products. Participants in the pilot safety cohort and the main cohort were assigned (1:1) by block randomisation to a study vaccine group. Participants in the pilot safety cohort received two doses of Pfs25H-EPA/Alhydrogel 16 μg or Euvax B (comparator vaccine), and participants in the main cohort received Pfs25H-EPA/Alhydrogel 47 μg or comparator vaccine (Euvax B for the first, second, and third vaccinations and Menactra for the fourth vaccination). Participants and investigators were masked to group assignment, and randomisation codes in sealed envelopes held by a site pharmacist. Vials with study drug for injection were covered by opaque tape and labelled with a study identification number. Group assignments were unmasked at final study visit. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. This trial is registered with ClinicalTrials.gov, number NCT01867463.Findings: Between May 15, and Jun 16, 2013, 230 individuals were screened for eligibility. 20 individuals were enrolled in the pilot safety cohort; ten participants were assigned to receive Pfs25H-EPA/Alhydrogel 16 μg, and ten participants were assigned to receive comparator vaccine. 100 individuals were enrolled in the main cohort; 50 participants were assigned to receive Pfs25H-EPA/Alhydrogel 47 μg, and 50 participants were assigned to receive comparator vaccine. Compared with comparator vaccinees, Pfs25H vaccinees had more solicited adverse events (137 events vs 86 events; p=0·022) and treatment-related adverse events (191 events vs 126 events, p=0·034), but the number of other adverse events did not differ between study vaccine groups (792 vs 683). Pfs25H antibody titres increased with each dose, with a peak geometric mean of 422·3 ELISA units (95% CI 290-615) after the fourth dose, but decreased relatively rapidly thereafter, with a half-life of 42 days for anti-Pfs25H and 59 days for anti-EPA (median ratio of titres at day 600 to peak, 0·19 for anti-Pfs25H vs 0·29 for anti-EPA; p=0·009). Serum transmission-reducing activity was greater for Pfs25H than for comparator vaccine after the fourth vaccine dose (p<0·001) but not after the third dose (p=0·09). Repeated direct skin feeds were well tolerated, but the number of participants who infected at least one mosquito did not differ between Pfs25H and comparator vaccinees after the fourth dose (p=1, conditional exact).Interpretation: Pfs25H-EPA/Alhydrogel was well tolerated and induced significant serum activity by standard membrane feeding assays but transmission blocking activity was not confirmed by weekly direct skin feed. This activity required four doses, and titres decreased rapidly after the fourth dose. Alternative antigens or combinations should be assessed to improve activity.Funding: Division of Intramural Research, National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali.Methods: After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18-35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov, number NCT01988636.Findings: Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three [7%] people in the vaccine group vs four [9%] in the placebo group) followed by fatigue (one [2%] person in the placebo group), fever (one [2%] person in the placebo group), and myalgia (one [2%] person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313-0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528-0·918) by proportional analysis (p=0·006).Interpretation: PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season.Funding: US National Institutes of Health Intramural Research Program, Sanaria. [ABSTRACT FROM AUTHOR]