RESUMEN
The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Hígado/inmunología , Hígado/parasitología , Vacunas contra la Malaria/inmunología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/inmunología , Vacunas Atenuadas/inmunología , Adulto , Animales , Formación de Anticuerpos/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Estadios del Ciclo de Vida/inmunología , Malaria/sangre , Malaria/inmunología , Malaria/parasitología , Malaria/prevención & control , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/química , Masculino , Persona de Mediana Edad , Plasmodium falciparum/crecimiento & desarrollo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , Vacunación/efectos adversos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/químicaRESUMEN
Placental accumulation of Plasmodium falciparum infected erythrocytes results in maternal anemia, low birth weight, and pregnancy loss. The parasite protein VAR2CSA facilitates the accumulation of infected erythrocytes in the placenta through interaction with the host receptor chondroitin sulfate A (CSA). Antibodies that prevent the VAR2CSA-CSA interaction correlate with protection from placental malaria, and VAR2CSA is a high-priority placental malaria vaccine antigen. Here, structure-guided design leveraging the full-length structures of VAR2CSA produced a stable immunogen that retains the critical conserved functional elements of VAR2CSA. The design expressed with a six-fold greater yield than the full-length protein and elicited antibodies that prevent adhesion of infected erythrocytes to CSA. The reduced size and adaptability of the designed immunogen enable efficient production of multiple variants of VAR2CSA for use in a cocktail vaccination strategy to increase the breadth of protection. These designs form strong foundations for the development of potent broadly protective placental malaria vaccines.
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum , Malaria , Humanos , Embarazo , Femenino , Placenta/metabolismo , Malaria Falciparum/parasitología , Anticuerpos Antiprotozoarios , Plasmodium falciparum/metabolismo , Antígenos de Protozoos , Sulfatos de Condroitina/metabolismo , Eritrocitos/parasitologíaRESUMEN
BACKGROUND: The extent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure and transmission in Mali and the surrounding region is not well understood. We aimed to estimate the cumulative incidence of SARS-CoV-2 in 3 communities and understand factors associated with infection. METHODS: Between July 2020 and January 2021, we collected blood samples and demographic, social, medical, and self-reported symptoms information from residents aged 6 months and older over 2 study visits. SARS-CoV-2 antibodies were measured using a highly specific 2-antigen enzyme-linked immunosorbent assay optimized for use in Mali. We calculated cumulative adjusted seroprevalence for each community and evaluated factors associated with serostatus at each visit by univariate and multivariate analysis. RESULTS: Overall, 94.8% (2533/2672) of participants completed both study visits. A total of 31.3% (837/2672) were aged <10 years, 27.6% (737/2672) were aged 10-17 years, and 41.1% (1098/2572) were aged ≥18 years. The cumulative SARS-CoV-2 exposure rate was 58.5% (95% confidence interval, 47.5-69.4). This varied between sites and was 73.4% in the urban community of Sotuba, 53.2% in the rural town of Bancoumana, and 37.1% in the rural village of Donéguébougou. Study site and increased age were associated with serostatus at both study visits. There was minimal difference in reported symptoms based on serostatus. CONCLUSIONS: The true extent of SARS-CoV-2 exposure in Mali is greater than previously reported and may now approach hypothetical "herd immunity" in urban areas. The epidemiology of the pandemic in the region may be primarily subclinical and within background illness rates.
RESUMEN
Inhabitants of the Greater Mekong Subregion in Cambodia are exposed to pathogens that might influence serologic cross-reactivity with severe acute respiratory syndrome coronavirus 2. A prepandemic serosurvey of 528 malaria-infected persons demonstrated higher-than-expected positivity of nonneutralizing IgG to spike and receptor-binding domain antigens. These findings could affect interpretation of large-scale serosurveys.
Asunto(s)
COVID-19 , Malaria , Anticuerpos Antivirales , Cambodia/epidemiología , Humanos , Malaria/epidemiología , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: False positivity may hinder the utility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests in sub-Saharan Africa. METHODS: From 312 Malian samples collected before 2020, we measured antibodies to the commonly tested SARS-CoV-2 antigens and 4 other betacoronaviruses by enzyme-linked immunosorbent assay (ELISA). In a subset of samples, we assessed antibodies to a panel of Plasmodium falciparum antigens by suspension bead array and functional antiviral activity by SARS-CoV-2 pseudovirus neutralization assay. We then evaluated the performance of an ELISA using SARS-CoV-2 spike protein and receptor-binding domain developed in the United States using Malian positive and negative control samples. To optimize test performance, we compared single- and 2-antigen approaches using existing assay cutoffs and population-specific cutoffs. RESULTS: Background reactivity to SARS-CoV-2 antigens was common in prepandemic Malian samples. The SARS-CoV-2 reactivity varied between communities, increased with age, and correlated negligibly/weakly with other betacoronavirus and P falciparum antibodies. No prepandemic samples demonstrated functional activity. Regardless of the cutoffs applied, test specificity improved using a 2-antigen approach. Test performance was optimal using a 2-antigen assay with population-specific cutoffs (sensitivity, 73.9% [95% confidence interval {CI}, 51.6-89.8]; specificity, 99.4% [95% CI, 97.7-99.9]). CONCLUSIONS: We have addressed the problem of SARS-CoV-2 seroassay performance in Africa by using a 2-antigen assay with cutoffs defined by performance in the target population.
Asunto(s)
Anticuerpos Antivirales/sangre , COVID-19/epidemiología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , COVID-19/sangre , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G , Malí/epidemiología , Sensibilidad y Especificidad , Glicoproteína de la Espiga del Coronavirus/químicaRESUMEN
BACKGROUND: Seasonal malaria chemoprevention (SMC) is a novel strategy to reduce malaria infections in children. Infection with Plasmodium falciparum results in immune dysfunction characterized by elevated expression of markers associated with exhaustion, such as PD1 and LAG3, and regulatory CD4+FOXP3+ T cells. METHODS: In the current study, the impact of seasonal malaria chemoprevention on malaria-induced immune dysfunction, as measured by markers associated with exhaustion and regulatory T cells, was explored by flow cytometry. RESULTS: Children that received seasonal malaria chemoprevention had fewer malaria episodes and showed significantly lower fold changes in CD4+PD1+ and CD4+PD1+LAG3+ compared to those that did not receive SMC. Seasonal malaria chemoprevention had no observable effect on fold changes in CD8 T cells expressing PD1 or CD160. However, children receiving SMC showed greater increases in CD4+FOXP3+ T regulatory cells compared to children not receiving SMC. CONCLUSIONS: These results provide important insights into the dynamics of malaria-induced changes in the CD4 T-cell compartment of the immune system and suggest that the reduction of infections due to seasonal malaria chemoprevention may also prevent immune dysfunction. CLINICAL TRIALS REGISTRATION: NCT02504918.
Asunto(s)
Antígenos CD/sangre , Antimaláricos/uso terapéutico , Linfocitos T CD4-Positivos/metabolismo , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Receptor de Muerte Celular Programada 1/sangre , Amodiaquina/uso terapéutico , Biomarcadores/sangre , Preescolar , Combinación de Medicamentos , Femenino , Factores de Transcripción Forkhead/sangre , Humanos , Lactante , Masculino , Pirimetamina/uso terapéutico , Estaciones del Año , Sulfadoxina/uso terapéutico , Linfocitos T Reguladores , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
BACKGROUND: Immunity that limits malarial disease is acquired over time, but adults living in endemic areas continue to become infected and can require treatment for clinical illness. Gamma delta (γδ) T cells, particularly the Vδ2+ subset, have been associated with development of clinical malaria in children. In this study, the dynamics of total γδ T cells, Vδ2+ and Vδ2- T cells were measured during a malaria transmission season in Malian adults. METHODS: This study explored γδ T cell dynamics and Plasmodium falciparum infection outcomes over the course of the malaria transmission season in Malian adults enrolled in the placebo arm of a double-blind randomized vaccine trial. All volunteers were treated with anti-malarial drugs prior to the start of the transmission season and blood smears were assessed for P. falciparum infection every 2 weeks from July 2014 to January 2015. The study participants were stratified as either asymptomatic infections or clinical malaria cases. Vδ2+ and Vδ2- γδ T cell frequencies and activation (as measured by CD38 expression) were measured in all study participants at baseline and then every 2 months using a whole blood flow cytometry assay. RESULTS: Forty of the forty-three subjects became infected with P. falciparum and, of those, 21 individuals were diagnosed with clinical malaria at least once during the season. The γδ T cell percentage and activation increased over the duration of the transmission season. Both the Vδ2+ and Vδ2- γδ T cells were activated by P. falciparum infection. CONCLUSION: γδ T cells increased during a malaria transmission season and this expansion was noted in both the Vδ2+ and Vδ2- γδ T cells. However, neither expansion or activation of either γδ T cell subsets discriminated study participants that had asymptomatic infections from those that had clinical malaria cases.
Asunto(s)
Linfocitos Intraepiteliales/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/patología , Plasmodium falciparum/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Células Sanguíneas , Femenino , Humanos , Estudios Longitudinales , Masculino , Malí , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
Whole-sporozoite vaccines confer sterilizing immunity to malaria-naive individuals by unknown mechanisms. In the first PfSPZ Vaccine trial ever in a malaria-endemic population, Vδ2 γδ T cells were significantly elevated and Vγ9/Vδ2 transcripts ranked as the most upregulated in vaccinees who were protected from Plasmodium falciparum infection. In a mouse model, absence of γδ T cells during vaccination impaired protective CD8 T cell responses and ablated sterile protection. γδ T cells were not required for circumsporozoite protein-specific Ab responses, and γδ T cell depletion before infectious challenge did not ablate protection. γδ T cells alone were insufficient to induce protection and required the presence of CD8α+ dendritic cells. In the absence of γδ T cells, CD8α+ dendritic cells did not accumulate in the livers of vaccinated mice. Altogether, our results show that γδ T cells were essential for the induction of sterile immunity during whole-organism vaccination.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Vacunas contra la Malaria/inmunología , Malaria/inmunología , Plasmodium falciparum/fisiología , Esporozoítos/inmunología , Linfocitos T/inmunología , Adulto , Animales , Anticuerpos Antiprotozoarios/sangre , Antígenos CD8/metabolismo , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Estudios de Seguimiento , Humanos , Inmunidad , Hígado/patología , Malaria/prevención & control , Malí , Ratones , Fragmentos de Péptidos/inmunología , Proteínas Protozoarias/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , VacunaciónRESUMEN
While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Infecciones por VIH/inmunología , VIH-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antirretrovirales/uso terapéutico , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/inmunología , Proliferación Celular , Femenino , Citometría de Flujo , Proteínas Ligadas a GPI/metabolismo , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Viremia/tratamiento farmacológico , Viremia/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
Malaria transmission-blocking vaccines (TBV) are designed to inhibit the sexual stage development of the parasite in the mosquito host and can play a significant role in achieving the goal of malaria elimination. Preclinical and clinical studies using protein-protein conjugates of leading TBV antigens Pfs25 and Pfs230 domain 1 (Pfs230D1) have demonstrated the feasibility of TBV. Nevertheless, other promising vaccine platforms for TBV remain underexplored. The recent success of mRNA vaccines revealed the potential of this technology for infectious diseases. We explored the mRNA platform for TBV development. mRNA constructs of Pfs25 and Pfs230D1 variously incorporating signal peptides (SP), GPI anchor, and Trans Membrane (TM) domain were assessed in vitro for antigen expression, and selected constructs were evaluated in mice. Only mRNA constructs with GPI anchor or TM domain that resulted in high cell surface expression of the antigens yielded strong immune responses in mice. These mRNA constructs generated higher transmission-reducing functional activity versus the corresponding alum-adjuvanted protein-protein conjugates used as comparators. Pfs25 mRNA with GPI anchor or TM maintained >99% transmission reducing activity through 126 days, the duration of the study, demonstrating the potential of mRNA platform for TBV.
RESUMEN
BACKGROUND: Plasmodium falciparum parasitaemia during pregnancy causes maternal, fetal, and infant mortality. Poor pregnancy outcomes are related to blood-stage parasite sequestration and the ensuing inflammatory response in the placenta, which decreases over successive pregnancies. A radiation-attenuated, non-replicating, whole-organism vaccine based on P falciparum sporozoites (PfSPZ Vaccine) has shown efficacy at preventing infection in African adults. Here, we aimed to examine vaccine safety and efficacy of the PfSPZ Vaccine in adults and women who anticipated conception. METHODS: Two randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18-35 years and MLSPZV4 included non-pregnant women aged 18-38 years who anticipated conception within a year of enrolment. In MLSPZV3, participants were stratified by village and randomly assigned (2:1) using block randomisation to receive three doses of 9â×â105 PfSPZ Vaccine or saline placebo at weeks 0, 1, and 4 (4-week schedule) or at weeks 0, 8, and 16 (16-week schedule) and a booster dose around 1 year later. In MLSPZV4, women received presumptive artemether-lumefantrine twice per day for 3 days 2 weeks before dose one and were randomly assigned (1:1:1) using block randomisation to receive three doses of 9â×â105 or 1·8â×â106 PfSPZ Vaccine or saline placebo all administered at weeks 0, 1, and 4 (4-week schedule). Participants in both studies received artemether-lumefantrine 2 weeks before dose three and additionally 2 weeks before dose four (booster dose) in MLSPZV3. Investigators and participants were masked to group assignment. The primary outcome, assessed in the as-treated population, was PfSPZ Vaccine safety and tolerability within 7 days after each dose. The secondary outcome, assessed in the modified intention-to-treat population, was vaccine efficacy against P falciparum parasitaemia (defined as the time-to-first positive blood smear) from dose three until the end of transmission season. In exploratory analyses, MLSPZV4 evaluated incidence of maternal obstetric and neonatal outcomes as safety outcomes, and vaccine efficacy against P falciparum parasitaemia during pregnancy (defined as time-to-first positive blood smear post-conception). In MLSPZV4, women were followed at least once a month with human chorionic gonadotropin testing, and those who became pregnant received standard of care (including intermittent presumptive sulfadoxine-pyrimethamine antimalarial drugs after the first trimester) during routine antenatal visits. These studies are registered with ClinicalTrials.gov, NCT03510481 and NCT03989102. FINDINGS: Participants were enrolled for vaccination during the onset of malaria seasons for two sequential studies conducted from 2018 to 2019 for MLSPZV3 and from 2019 to 2021 for MLSPZV4, with follow-up during malaria seasons across 2 years. In MLSPZV3, 478 adults were assessed for eligibility, of whom 220 were enrolled between May 30 and June 12, 2018, and then between Aug 13 and Aug 18, 2018, and 210 received dose one. 66 (96%) of 69 participants who received the 16-week schedule and 68 (97%) of 70 who received the 4-week schedule of the 9â×â105 PfSPZ Vaccine and 70 (99%) of 71 who received saline completed all three doses in year 1. In MLSPZV4, 407 women were assessed for eligibility, of whom 324 were enrolled from July 3 to July 27, 2019, and 320 received dose one of presumptive artemether-lumefantrine. 300 women were randomly assigned with 100 per group (PfSPZ Vaccine 9â×â105, 1·8â×â106, or saline) receiving dose one. First trimester miscarriages were the most commonly reported serious adverse event but occurred at a similar rate across study groups (eight [15%] of 54 with 9â×â105 PfSPZ Vaccine, 12 [21%] of 58 with 1·8â×â106 PfSPZ Vaccine, and five [12%] of 43 with saline). One unrelated maternal death occurred 425 days after the last vaccine dose in the 1·8â×â106 PfSPZ Vaccine group due to peritonitis shortly after childbirth. Most related adverse events reported in MLSPZV3 and MLSPZV4 were mild (grade 1) and frequency of adverse events in the PfSPZ Vaccine groups did not differ from that in the saline group. Two unrelated serious adverse events occurred in MLSPZV3 (one participant had appendicitis in the 9â×â105 PfSPZ Vaccine group and the other in the saline group died due to a road traffic accident). In MLSPZV3, the 9â×â105 PfSPZ Vaccine did not show vaccine efficacy against parasitaemia with the 4-week (27% [95% CI -18 to 55] in year 1 and 42% [-5 to 68] in year 2) and 16-week schedules (16% [-34 to 48] in year 1 and -14% [-95 to 33] in year 2); efficacies were similar or worse against clinical malaria compared with saline. In MLSPZV4, the PfSPZ Vaccine showed significant efficacy against parasitaemia at doses 9â×â105 (41% [15 to 59]; p=0·0069 in year 1 and 61% [36 to 77]; p=0·0011 in year 2) and 1·8â×â106 (54% [34 to 69]; p<0·0001 in year 1 and 45% [13 to 65]; p=0·029 in year 2); and against clinical malaria at doses 9â×â105 (47% [20 to 65]; p=0·0045 in year 1 and 56% [22 to 75]; p=0·0081 in year 2) and 1·8â×â106 (48% [22 to 65]; p=0·0013 in year 1 and 40% [2 to 64]; p=0·069 in year 2). Vaccine efficacy against post-conception P falciparum parasitaemia during first pregnancies that arose in the 2-year follow-up was 57% (14 to 78; p=0·017) in the 9 × 105 PfSPZ Vaccine group versus 49% (3 to 73; p=0·042) in the 1·8â×â106 PfSPZ Vaccine group. Among 55 women who became pregnant within 24 weeks after dose three, vaccine efficacy against parasitaemia was 65% (23 to 84; p=0·0088) with the 9â×â105 PfSPZ Vaccine and 86% (64 to 94; p<0·0001) with the 1·8â×â106 PfSPZ Vaccine. When combined in a post-hoc analysis, women in the PfSPZ Vaccine groups had a non-significantly reduced time-to-first pregnancy after dose one compared with those in the saline group (log-rank test p=0·056). Exploratory maternal obstetric and neonatal outcomes did not differ significantly between vaccine groups and saline. INTERPRETATION: PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9â×â105 and 1·8â×â106 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.
RESUMEN
BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown.METHODSThis randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/µL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later.RESULTSThere were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies.CONCLUSIONSPfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.TRIAL REGISTRATIONClinicalTrials.gov NCT03420053.FUNDINGEquatorial Guinea Malaria Vaccine Initiative (EGMVI), made up of the Government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon Equatorial Guinea Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG; Swiss government, through ESKAS scholarship grant no. 2016.0056; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH grant 1U01AI155354-01.
Asunto(s)
Infecciones por VIH , Vacunas contra la Malaria , Malaria Falciparum , Adolescente , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Anticuerpos Antiprotozoarios , Pueblo de África Oriental , Infecciones por VIH/complicaciones , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum , Tanzanía , Seronegatividad para VIH , Seropositividad para VIH , Eficacia de las VacunasRESUMEN
The spread of SARS-CoV-2 cannot be well monitored and understood in areas without capacity for effective disease surveillance. Countries with a young population will have disproportionately large numbers of asymptomatic or pauci-symptomatic infections, further hindering detection of infection in the population. Sero-surveillance on a country-wide scale by trained medical professionals may be limited in scope in resource limited setting such as Mali. Novel ways of broadly sampling the human population in a non-invasive method would allow for large-scale surveillance at a reduced cost. Here we evaluate the collection of naturally bloodfed mosquitoes to test for human anti-SARS-CoV-2 antibodies in the laboratory and at five field locations in Mali. Immunoglobulin-G antibodies were found to be readily detectable within the mosquito bloodmeals by a bead-based immunoassay at least through 10 hours post-feeding with high sensitivity (0.900 ± 0.059) and specificity (0.924 ± 0.080), respectively, indicating that most blood-fed mosquitoes collected indoors during early morning hours (and thus, have likely fed the previous night) are viable samples for analysis. We find that reactivity to four SARS-CoV-2 antigens rose during the pandemic from pre-pandemic levels. Consistent with other sero-surveillance studies in Mali, crude seropositivity of blood sampled via mosquitoes was 6.3% in October/November 2020 over all sites, and increased to 25.1% overall, with the town closest to Bamako reaching 46.7% in February of 2021. Mosquito bloodmeals a viable target for conventional immunoassays, and therefore country-wide sero-surveillance of human diseases (both vector-borne and non-vector-borne) is attainable in areas where human-biting mosquitoes are common, and is an informative, cost-effective, non-invasive sampling option.
RESUMEN
Malaria transmission-blocking vaccine candidates Pfs25-EPA and Pfs230D1-EPA target sexual stage development of Plasmodium falciparum parasites in the mosquito host, thereby reducing mosquito infectivity. When formulated on Alhydrogel, Pfs25-EPA has demonstrated safety and immunogenicity in a phase 1 field trial, while Pfs230D1-EPA has shown superior activity to Pfs25-EPA in a phase 1 US trial and has entered phase 2 field trials. Development continues to enhance immunogenicity of these candidates toward producing a vaccine to reduce malaria transmission (VRMT) with both pre-erythrocytic (i.e., anti-infection) and transmission-blocking components. GSK Adjuvant Systems have demonstrated successful potency in pre-erythrocytic vaccine trials and might offer a common platform for VRMT development. Here, we describe preclinical evaluations of Pfs25-EPA and Pfs230D1-EPA nanoparticles with GSK platforms. Formulations were stable after a series of assessments and induced superior antibody titers and functional activity in CD-1 mice, compared to Alhydrogel formulations of the same antigens.
RESUMEN
Background: The spread of SARS-CoV-2 cannot be well monitored and understood in areas without capacity for effective disease surveillance. Countries with a young population will have disproportionately large numbers of asymptomatic or pauci-symptomatic infections, further hindering detection of infection. Sero-surveillance on a country-wide scale by trained medical professionals may be limited in a resource-limited setting such as Mali. Novel ways of broadly sampling the human population in a non-invasive method would allow for large-scale surveillance at a reduced cost. Approach: Here we evaluate the collection of naturally blood-fed mosquitoes to test for human anti-SARS-CoV-2 antibodies in the laboratory and at five field locations in Mali. Results: Immunoglobulin-G antibodies to multiple SARS-CoV-2 antigens were readily detected in mosquito bloodmeals by bead-based immunoassay through at least 10â h after feeding [mean sensitivity of 0.92 (95% CI 0.78-1) and mean specificity of 0.98 (95% CI 0.88-1)], indicating that most blood-fed mosquitoes collected indoors during early morning hours (and likely to have fed the previous night) are viable samples for analysis. We found that reactivity to four SARS-CoV-2 antigens rose during the pandemic from pre-pandemic levels. The crude seropositivity of blood sampled via mosquitoes was 6.3% in October and November 2020 across all sites, and increased to 25.1% overall by February 2021, with the most urban site reaching 46.7%, consistent with independent venous blood-based sero-surveillance estimates. Conclusions: We have demonstrated that using mosquito bloodmeals, country-wide sero-surveillance of human diseases (both vector-borne and non-vector-borne) is possible in areas where human-biting mosquitoes are common, offering an informative, cost-effective, and non-invasive sampling option.
RESUMEN
BACKGROUND: Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults. Here, we compared these vaccines in malaria-experienced Malians. METHODS: We did a pilot safety study then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 18-50-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 4·5, and 16·5 of either 47 µg Pfs25, 40 µg Pfs230D1 or comparator (Twinrix or Menactra)-all co-administered with normal saline for blinding-or 47 µg Pfs25 plus 40 µg Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). This trial is registered at ClinicalTrials.gov, NCT02334462. FINDINGS: Between March 19, and June 2, 2015, we screened 471 individuals. Of 225 enrolled for the pilot and main cohorts, we randomly assigned 25 participants to pilot safety cohort groups of five (20%) to receive a two-dose series of Pfs25-EPA/Alhydrogel (16 µg), Pfs230D1-EPA/Alhydrogel (15 µg) or comparator, followed by Pfs25-EPA/Alhydrogel (16 µg) plus Pfs230D1-EPA/Alhydrogel (15 µg) or comparator plus saline. For the main cohort, we enrolled 200 participants between May 11 and June 2, 2015, to receive a four-dose series of 47 µg Pfs25-EPA/Alhydrogel plus saline (n=50 [25%]; Pfs25), 40 µg Pfs230D1-EPA/Alhydrogel plus saline (n=49 [25%]; Pfs230D1), 47 µg Pfs25-EPA/Alhydrogel plus 40 µg Pfs230D1-EPA/Alhydrogel (n=50 [25%]; Pfs25 plus Pfs230D1), or comparator (Twinrix or Menactra) plus saline (n=51 [25%]). Vaccinations were well tolerated in the pilot safety and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter (Pfs230D1 geometric mean: 77·8 [95% CI 56·9-106·3], 146·4 [108·3-198·0], and 410·2 [301·6-558·0]; Pfs25 geometric mean 177·7 [130·3-242·4] and 315·7 [209·9-474·6]). Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 (74·5% [66·6-82·5]) and Pfs25 plus Pfs230D1 (68·6% [57·3-79·8]), after the third dose and after the fourth dose (88·9% [81·7-96·2] for Pfs230D1 and 85·0% [78·4-91·5] Pfs25 plus Pfs230D1) but not for Pfs25 (58·2% [49·1-67·3] after the third dose and 58·2% [48·5-67·9] after the fourth dose). Pfs230D1 transmission-reducing activity (73·7% [64·1-83·3]) persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups (Pfs25 33 [3%] of 982 [-0·013 to 0·014], Pfs230D1 22 [2%] of 954 [-0·005 to 0·027], and combination 11 [1%] of 940 [-0·024 to 0·002]) did not differ from that of the comparator (22 [2%] of 974), nor did Pfs230D1 and combination groups differ (-0·024 to 0·001). INTERPRETATION: Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness. FUNDING: Intramural Research Program of the National Institute of Allergy and Infectious Diseases and US National Institutes of Health.
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum , Vacunas Meningococicas , Animales , Adulto , Humanos , Adolescente , Adulto Joven , Persona de Mediana Edad , Hidróxido de Aluminio , Plasmodium falciparum , Vacunas contra la Malaria/efectos adversos , Método Doble Ciego , Inmunogenicidad VacunalRESUMEN
Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.
Asunto(s)
COVID-19 , Malaria , Formación de Anticuerpos , Infecciones Asintomáticas/epidemiología , COVID-19/epidemiología , Humanos , Malaria/epidemiología , Malí/epidemiología , Pandemias , Parasitemia/epidemiologíaRESUMEN
BACKGROUND: WHO recently approved a partially effective vaccine that reduces clinical malaria in children, but increased vaccine activity is required to pursue malaria elimination. A phase 1 clinical trial was done in Mali, west Africa, to assess the safety, immunogenicity, and protective efficacy of a three-dose regimen of Plasmodium falciparum sporozoite (PfSPZ) Vaccine (a metabolically active, non-replicating, whole malaria sporozoite vaccine) against homologous controlled human malaria infection (CHMI) and natural P falciparum infection. METHODS: We recruited healthy non-pregnant adults aged 18-50 years in Donéguébougou, Mali, and surrounding villages (Banambani, Toubana, Torodo, Sirababougou, Zorokoro) for an open-label, dose-escalation pilot study and, thereafter, a randomised, double-blind, placebo-controlled main trial. Pilot study participants were enrolled on an as-available basis to one group of CHMI infectivity controls and three staggered vaccine groups receiving: one dose of 4·5 × 105, one dose of 9 × 105, or three doses of 1·8 × 106 PfSPZ via direct venous inoculation at approximately 8 week intervals, followed by homologous CHMI 5 weeks later with infectious PfSPZ by direct venous inoculation (PfSPZ Challenge). Main cohort participants were stratified by village and randomly assigned (1:1) to receive three doses of 1·8 × 106 PfSPZ or normal saline at 1, 13, and 19 week intervals using permuted block design by the study statistician. The primary outcome was safety and tolerability of at least one vaccine dose; the secondary outcome was vaccine efficacy against homologous PfSPZ CHMI (pilot study) or against naturally transmitted P falciparum infection (main study) measured by thick blood smear. Combined artesunate and amodiaquine was administered to eliminate pre-existing parasitaemia. Outcomes were analysed by modified intention to treat (mITT; including all participants who received at least one dose of investigational product; safety and vaccine efficacy) and per protocol (vaccine efficacy). This trial is registered with ClinicalTrials.gov, number NCT02627456. FINDINGS: Between Dec 20, 2015, and April 30, 2016, we enrolled 56 participants into the pilot study (five received the 4·5 × 105 dose, five received 9 × 105, 30 received 1·8 × 106, 15 were CHMI controls, and one withdrew before vaccination) and 120 participants into the main study cohort with 60 participants assigned PfSPZ Vaccine and 60 placebo in the main study. Adverse events and laboratory abnormalities post-vaccination in all dosing groups were few, mainly mild, and did not differ significantly between vaccine groups (all p>0·05). Unexpected severe transaminitis occured in four participants: one participant in pilot phase that received 1·8 × 106 PfSPZ Vaccine, one participant in main phase that received 1·8 × 106 PfSPZ Vaccine, and two participants in the main phase placebo group. During PfSPZ CHMI, approximately 5 weeks after the third dose of 1·8 × 106 PfSPZ, none of 29 vaccinees and one of 15 controls became positive on thick blood smear; subsequent post-hoc PCR analysis for submicroscopic blood stage infections detected P falciparum parasites in none of the 29 vaccine recipients and eight of 15 controls during CHMI. In the main trial, 32 (58%) of 55 vaccine recipients and 42 (78%) of 54 controls became positive on thick blood smear during 24-week surveillance after vaccination. Vaccine efficacy (1-hazard ratio) was 0·51 per protocol (95% CI 0·20-0·70; log-rank p=0·0042) and 0·39 by mITT (0·04-0·62; p=0·033); vaccine efficacy (1-risk ratio) was 0·24 per-protocol (0·02-0·41; p=0·031) and 0·22 mITT (0·01-0·39; p=0·041). INTERPRETATION: A three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial. FUNDING: US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Sanaria. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum , Malaria , Adolescente , Adulto , Animales , Niño , Método Doble Ciego , Humanos , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Malí , Persona de Mediana Edad , Proyectos Piloto , Plasmodium falciparum , Estaciones del Año , Esporozoítos , Adulto JovenRESUMEN
While well documented in human immunodeficiency virus (HIV)-1, neurologic sequelae have not been systematically evaluated in HIV-2. After excluding for confounding comorbidities, 67 individuals from a rural cohort in Guinea-Bissau (22 HIV-2 participants, 45 seronegative controls) were evaluated. HIV + individuals were divided into CD4 < 350 and CD4 ≥ 350 for analysis. HIV-associated neurocognitive disorders (HAND), assessed by the International HIV Dementia Scale (IHDS), distal sensory polyneuropathy (DSPN), and myelopathy were the main outcome variables. In univariate analysis, there was no difference in IHDS scores among groups. When analyzed by primary education attainment, IHDS scores were nonsignificantly higher (p = 0.06) with more education. There was no significant difference in DSPN prevalence among groups; overall, 45% of participants had DSPN. There were no cases of myelopathy. In multivariate linear regression, higher IHDS scores were significantly correlated with older age (coefficient = -0.11, p < 0.001). Logistic regression analysis showed that older age (odds ratio (OR) 95% CI 1.04-1.20), lower CD4 count (OR 95% CI 0.996-0.999), and higher BMI (OR 95% CI 1.02-1.43) significantly predicted the presence of DSPN. While a significant increase in cognitive impairment was not observed in HIV-2-infected individuals, the study suggests the IHDS may be a less effective screening tool for HAND in settings of lower educational attainment as encountered in rural Guinea-Bissau. Similar to HIV-1, DSPN seems to occur with lower CD4 counts in HIV-2. Further study of the viral-host interactions in HIV-2 and its consequent neurological diseases may provide an avenue for understanding the epidemic problems of HIV-1.