Milagritos Tapia | University of Maryland Baltimore (original) (raw)
Papers by Milagritos Tapia
JAMA Network Open
ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unpr... more ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts.ObservationsTo support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing...
The American journal of tropical medicine and hygiene, 2005
As infants lose maternally derived antibody, they experience a period when antibody levels are in... more As infants lose maternally derived antibody, they experience a period when antibody levels are insufficient to protect against measles yet may interfere with immunization. In Kangaba Mali, sera were collected from 89 2-8-month-old infants and 32 9-10-month-old infants without a history of measles or vaccination; post-vaccination sera were collected from 24 of the 9-10-month-old infants 3-5 weeks after receiving measles vaccine. Measles antibody was measured by plaque reduction neutralization (PRN) and enzyme linked immunosorbent assay. At two months of age, 30% had protective PRN titers; among six-month-old infants, none had protective titers. Prior to vaccination, 16% of 9-10-month-old infants exhibited protective titers; all demonstrated protective titers post-vaccination. The early onset of the window of vulnerability in Kangaba infants likely reflects the changing ecology of measles in Africa. Ways to protect these vulnerable infants against measles must be devised.
The Journal of infectious diseases, Jan 15, 2015
Vaccine, Jan 27, 2012
The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rota... more The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥ 11 using the Vesikari Clinical Scoring System occurring ≥ 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 19...
Clinical and vaccine immunology : CVI, 2011
A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects... more A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 an...
Pediatric Infectious Disease Journal, 2006
Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow ... more Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow evaluation of immunization services in developing countries. Measurement of IgG tetanus antitoxin in oral fluid was investigated as a practical and noninvasive alternative to and correlate of serum antibodies. Serum and oral fluid were collected from Malian infants, toddlers and adults (males without a history of tetanus vaccination). Specific IgG tetanus antitoxin was measured by enzyme-linked immunosorbent assay in serum (S-ELISA) and oral fluid (OF-ELISA). One hundred forty-two pairs of serum and oral fluid samples were collected from infants, 35 pairs from toddlers and 35 pairs from adults. IgG tetanus antitoxin titers measured by OF-ELISA were 100-fold lower than those measured by S-ELISA but they correlated strongly (r = 0.90, P < 0.001). All 35 toddlers who had received 2 or 3 doses of diphtheria-tetanus-pertussis (DTP) vaccine (100%) had serum tetanus antitoxin levels >or=0.15 IU/mL and 28 of 35 (80%) had oral fluid values >or=0.0015 IU/mL. Among adults lacking a history of tetanus immunization, only 6 of 35 (17.1%) had serum titers >or=0.15 IU/mL and 4 of 35 (11%) had oral fluid titers >or=0.0015 IU/mL in oral fluid. IgG tetanus antitoxin in oral fluid correlates well with levels in serum. OF-ELISA values >or=0.0015 IU/mL constitute protection against tetanus and in subjects >12 months of age imply multiple prior contacts with immunization services. IgG tetanus antitoxin measured by OF-ELISA provides a logistically practical alternative for performing seroprevalence surveys.
Vaccine, 2012
The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq ® , was evaluated in a double-bl... more The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq ® , was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (in 3 lowincome countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine.
Vaccine, 2012
The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rota... more The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥11 using the Vesikari Clinical Scoring System occurring ≥14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: −431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: −125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: −23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (≥3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the postthird dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related.
Vaccine, 2012
Background: We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAV... more Background: We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAVIeligible Asian countries, Bangladesh and Vietnam, nested in a larger randomized, double-blind, placebocontrolled efficacy trial conducted over a two-year period from 2007 through 2009. Methods: 2036 infants were randomly assigned, in a 1:1 ratio, to receive three oral doses of PRV or placebo approximately at 6, 10, and 14 weeks of age. Concomitant use of EPI vaccines, including oral poliovirus vaccine (OPV) and diphtheria-tetanus-whole cell pertussis (DTwP) vaccine, was encouraged in accordance to the local EPI schedule. A total of 303 infants were evaluated for immunogenicity and blood samples were collected before the first dose (pD1) and approximately 14 days following the third dose (PD3). The seroresponse rates (≥3-fold rise from pD1 to PD3) and geometric mean titers (GMTs) were measured for anti-rotavirus immunoglobulin A (IgA) and serum neutralizing antibody (SNA) to human rotavirus serotypes G1, G2, G3, G4, and P1A[8], respectively. Results: Nearly 88% of the subjects showed a ≥3-fold increase in serum anti-rotavirus IgA response in the analysis of the two countries combined. When analyzed separately, the IgA response was lower in Bangladeshi children (78.1% [95% CI: 66.0, 87.5]) than in Vietnamese children (97.0% [95% CI: 89.6, 99.6]), with a PD3 GMT of 29.1 (units/mL) and 158.5 (units/mL), respectively. In the combined population, the SNA responses to the individual serotypes tested ranged from 10 (G3) to 50 (G1) percentage points lower than the responses shown in the developed countries. However, the SNA response to G3 in Vietnamese subjects was 37.3% (95% CI: 25.8, 50.0), which was similar to the G3 response rate in developed countries. Conclusions: Three oral doses of PRV were immunogenic in two GAVI-eligible Asian countries: Bangladesh and Vietnam. The GMTs of both the serum anti-rotavirus IgA and SNA responses were generally higher in Vietnamese than in Bangladeshi children. The SNA responses varied by individual serotypes and were lower than the results from developed countries. The clinical significance of these observations is not understood because an immune correlate of protection has not been established. 131 131 131 131 131 132 132 132 132 132 GMT (dilution units) and 95% CI 95.5
Tropical Infectious Diseases: Principles, Pathogens and Practice, 2011
The Pediatric Infectious Disease Journal, 2014
Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease ... more Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease (RHD) in developing countries. We sought to identify guidelines for empiric treatment of pharyngitis in low resource settings. To inform the design of GAS vaccines, we determined the emm types associated with pharyngitis among African schoolchildren. Surveillance for pharyngitis was conducted among children 5 to 16 years of age attending schools in Bamako, Mali. Students were encouraged to visit a study clinician when they had a sore throat. Enrollees underwent evaluation and throat swab for isolation of GAS. Strains were emm typed by standard methods. GAS was isolated from 449 (25.5%) of the 1,759 sore throat episodes. Painful cervical adenopathy identified 403 children (89.8%) with GAS infection and was absent in 369 uninfected children (28.2%). Emm type was determined in 396 (88.2%) of the 449 culture-positive children; 70 types were represented and 14 types accounted for 49% of isolates. Based on the proportion of the 449 isolates bearing emm types included in the 30-valent vaccine (31.0%) plus non-vaccine types previously shown to react to vaccine-induced bactericidal antibodies (44.1%), the vaccine could protect against almost 75% of GAS infections among Bamako schoolchildren. Two promising strategies could reduce RHD in low resource settings. Administering antibiotics to children with sore throat and tender cervical adenopathy could treat most GAS-positive children while reducing use of unnecessary antibiotics for uninfected children. Broad coverage against M types associated with pharyngitis in Bamako schoolchildren might be achieved with the 30-valent GAS vaccine under development.
Tropical Medicine & International Health, 2008
objective To study the effectiveness of the Haemophilus influenzae type b (Hib) vaccination progr... more objective To study the effectiveness of the Haemophilus influenzae type b (Hib) vaccination program in Uganda.
PLoS ONE, 2012
Background: Maternal immunization has gained traction as a strategy to diminish maternal and youn... more Background: Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.
PLoS Neglected Tropical Diseases, 2010
Background: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cau... more Background: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cause of invasive disease (bacteremia and focal infections such as meningitis) in infants and young children. Importantly, including data from Mali, three serovars, Salmonella enterica serovar Typhimurium, Salmonella Enteritidis and Salmonella Dublin, account for the majority of non-typhoidal Salmonella isolated from these patients.
The Pediatric Infectious Disease Journal, 2002
Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of... more Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of a 10-year-old child with influenza B encephalitis and profound weakness who was treated with oseltamivir is presented. This case illustrates several of the unusual findings associated with influenza infections and the result of treatment of influenza B encephalitis with oseltamivir.
The Pediatric Infectious Disease Journal, 2005
Population-based, bacteriologically confirmed disease burden data aid decision makers in African ... more Population-based, bacteriologically confirmed disease burden data aid decision makers in African countries pondering whether to introduce Haemophilus influenzae type b (Hib) immunization for infants. A bacteriology laboratory was established in Hopital Gabriel Toure, serving Bamako, Mali. Children age 0-15 years with fever &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =39 degrees C or syndromes compatible with invasive bacterial disease (meningitis, etc.) were eligible. From 2 to 5 mL of blood or relevant body fluid were inoculated into Bactec Ped Plus/F medium for automated culture; body fluids were also inoculated directly onto solid media. Hib was confirmed by standard microbiologic techniques and antibiograms generated by disk diffusion. From June 1, 2002 to May 31, 2004, 3592 (87.8%) of 4092 children admitted to Hopital Gabriel Toure with high fever or suspected invasive bacterial disease were cultured, including 1745 who were 0-11 months old, 1132 who were 1-4 years old and 715 who were 5-15 years old. Hib was isolated from 207 Bamako children, 81 from blood alone and 124 from cerebrospinal fluid (with or without positive blood culture). Of 207 cases 204 (98.5%) occurred in children younger than age 5 years (annual incidence, 45.2/10) and 159 (77%) in infants age 0-11 months (annual incidence, 158.4/10). Peak incidence (370.0 cases/10) and 12 of 21 Hib deaths occurred in 6- to 7-month-olds. Of the Hib isolates, 11.1% were resistant to ampicillin, 32% to chloramphenicol and 0.5% to ceftriaxone. The substantial burden of invasive Hib disease documented in Bamako has prompted the Malian government to introduce routine infant immunization with Hib conjugate.
The Pediatric Infectious Disease Journal, 2004
Prevention of invasive pneumococcal disease (IPD) in children is a global public health priority,... more Prevention of invasive pneumococcal disease (IPD) in children is a global public health priority, and determination of the most common serotypes is crucial for vaccine development and implementation. We performed prospective surveillance for IPD in hospitalized children in Bamako, Mali. All febrile children and others suspected to have invasive bacterial disease had an admission blood culture and cultures of additional anatomic sites when indicated. Standard microbiologic methods were used to identify, serotype and determine antibiograms for pneumococcal isolates. Of 2,049 children enrolled, 106 (5%) had an IPD, including 47 cases of meningitis and 44 bacteremic pneumonias. The incidence was highest in infants (84/100,000/year). The overall IPD case fatality rate was 24%. Only 2 of 96 isolates were nonsusceptible to penicillin. The serotypes isolated were 5 (54%), 2 (14%), 7F (10%), 19F (8%), 6A/B (3%), 9V (3%), 1 (2%) and 14 (1%). IPD is common and frequently fatal among hospitalized children in Mali, but surprisingly little resistance has occurred. Notably, 91% of the serotypes causing IPD in Bamako children are found in the 11-valent pneumococcal conjugate vaccine.
The Pediatric Infectious Disease Journal, 2006
Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow ... more Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow evaluation of immunization services in developing countries. Measurement of IgG tetanus antitoxin in oral fluid was investigated as a practical and noninvasive alternative to and correlate of serum antibodies. Serum and oral fluid were collected from Malian infants, toddlers and adults (males without a history of tetanus vaccination). Specific IgG tetanus antitoxin was measured by enzyme-linked immunosorbent assay in serum (S-ELISA) and oral fluid (OF-ELISA). One hundred forty-two pairs of serum and oral fluid samples were collected from infants, 35 pairs from toddlers and 35 pairs from adults. IgG tetanus antitoxin titers measured by OF-ELISA were 100-fold lower than those measured by S-ELISA but they correlated strongly (r = 0.90, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). All 35 toddlers who had received 2 or 3 doses of diphtheria-tetanus-pertussis (DTP) vaccine (100%) had serum tetanus antitoxin levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 28 of 35 (80%) had oral fluid values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL. Among adults lacking a history of tetanus immunization, only 6 of 35 (17.1%) had serum titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 4 of 35 (11%) had oral fluid titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL in oral fluid. IgG tetanus antitoxin in oral fluid correlates well with levels in serum. OF-ELISA values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL constitute protection against tetanus and in subjects &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;12 months of age imply multiple prior contacts with immunization services. IgG tetanus antitoxin measured by OF-ELISA provides a logistically practical alternative for performing seroprevalence surveys.
New England Journal of Medicine, 2011
JAMA Network Open
ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unpr... more ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts.ObservationsTo support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing...
The American journal of tropical medicine and hygiene, 2005
As infants lose maternally derived antibody, they experience a period when antibody levels are in... more As infants lose maternally derived antibody, they experience a period when antibody levels are insufficient to protect against measles yet may interfere with immunization. In Kangaba Mali, sera were collected from 89 2-8-month-old infants and 32 9-10-month-old infants without a history of measles or vaccination; post-vaccination sera were collected from 24 of the 9-10-month-old infants 3-5 weeks after receiving measles vaccine. Measles antibody was measured by plaque reduction neutralization (PRN) and enzyme linked immunosorbent assay. At two months of age, 30% had protective PRN titers; among six-month-old infants, none had protective titers. Prior to vaccination, 16% of 9-10-month-old infants exhibited protective titers; all demonstrated protective titers post-vaccination. The early onset of the window of vulnerability in Kangaba infants likely reflects the changing ecology of measles in Africa. Ways to protect these vulnerable infants against measles must be devised.
The Journal of infectious diseases, Jan 15, 2015
Vaccine, Jan 27, 2012
The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rota... more The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥ 11 using the Vesikari Clinical Scoring System occurring ≥ 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 19...
Clinical and vaccine immunology : CVI, 2011
A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects... more A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 an...
Pediatric Infectious Disease Journal, 2006
Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow ... more Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow evaluation of immunization services in developing countries. Measurement of IgG tetanus antitoxin in oral fluid was investigated as a practical and noninvasive alternative to and correlate of serum antibodies. Serum and oral fluid were collected from Malian infants, toddlers and adults (males without a history of tetanus vaccination). Specific IgG tetanus antitoxin was measured by enzyme-linked immunosorbent assay in serum (S-ELISA) and oral fluid (OF-ELISA). One hundred forty-two pairs of serum and oral fluid samples were collected from infants, 35 pairs from toddlers and 35 pairs from adults. IgG tetanus antitoxin titers measured by OF-ELISA were 100-fold lower than those measured by S-ELISA but they correlated strongly (r = 0.90, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). All 35 toddlers who had received 2 or 3 doses of diphtheria-tetanus-pertussis (DTP) vaccine (100%) had serum tetanus antitoxin levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 28 of 35 (80%) had oral fluid values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL. Among adults lacking a history of tetanus immunization, only 6 of 35 (17.1%) had serum titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 4 of 35 (11%) had oral fluid titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL in oral fluid. IgG tetanus antitoxin in oral fluid correlates well with levels in serum. OF-ELISA values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL constitute protection against tetanus and in subjects &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;12 months of age imply multiple prior contacts with immunization services. IgG tetanus antitoxin measured by OF-ELISA provides a logistically practical alternative for performing seroprevalence surveys.
Vaccine, 2012
The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq ® , was evaluated in a double-bl... more The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq ® , was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (in 3 lowincome countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine.
Vaccine, 2012
The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rota... more The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥11 using the Vesikari Clinical Scoring System occurring ≥14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: −431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: −125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: −23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (≥3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the postthird dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related.
Vaccine, 2012
Background: We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAV... more Background: We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAVIeligible Asian countries, Bangladesh and Vietnam, nested in a larger randomized, double-blind, placebocontrolled efficacy trial conducted over a two-year period from 2007 through 2009. Methods: 2036 infants were randomly assigned, in a 1:1 ratio, to receive three oral doses of PRV or placebo approximately at 6, 10, and 14 weeks of age. Concomitant use of EPI vaccines, including oral poliovirus vaccine (OPV) and diphtheria-tetanus-whole cell pertussis (DTwP) vaccine, was encouraged in accordance to the local EPI schedule. A total of 303 infants were evaluated for immunogenicity and blood samples were collected before the first dose (pD1) and approximately 14 days following the third dose (PD3). The seroresponse rates (≥3-fold rise from pD1 to PD3) and geometric mean titers (GMTs) were measured for anti-rotavirus immunoglobulin A (IgA) and serum neutralizing antibody (SNA) to human rotavirus serotypes G1, G2, G3, G4, and P1A[8], respectively. Results: Nearly 88% of the subjects showed a ≥3-fold increase in serum anti-rotavirus IgA response in the analysis of the two countries combined. When analyzed separately, the IgA response was lower in Bangladeshi children (78.1% [95% CI: 66.0, 87.5]) than in Vietnamese children (97.0% [95% CI: 89.6, 99.6]), with a PD3 GMT of 29.1 (units/mL) and 158.5 (units/mL), respectively. In the combined population, the SNA responses to the individual serotypes tested ranged from 10 (G3) to 50 (G1) percentage points lower than the responses shown in the developed countries. However, the SNA response to G3 in Vietnamese subjects was 37.3% (95% CI: 25.8, 50.0), which was similar to the G3 response rate in developed countries. Conclusions: Three oral doses of PRV were immunogenic in two GAVI-eligible Asian countries: Bangladesh and Vietnam. The GMTs of both the serum anti-rotavirus IgA and SNA responses were generally higher in Vietnamese than in Bangladeshi children. The SNA responses varied by individual serotypes and were lower than the results from developed countries. The clinical significance of these observations is not understood because an immune correlate of protection has not been established. 131 131 131 131 131 132 132 132 132 132 GMT (dilution units) and 95% CI 95.5
Tropical Infectious Diseases: Principles, Pathogens and Practice, 2011
The Pediatric Infectious Disease Journal, 2014
Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease ... more Group A streptococcus (GAS) pharyngitis is associated with high rates of rheumatic heart disease (RHD) in developing countries. We sought to identify guidelines for empiric treatment of pharyngitis in low resource settings. To inform the design of GAS vaccines, we determined the emm types associated with pharyngitis among African schoolchildren. Surveillance for pharyngitis was conducted among children 5 to 16 years of age attending schools in Bamako, Mali. Students were encouraged to visit a study clinician when they had a sore throat. Enrollees underwent evaluation and throat swab for isolation of GAS. Strains were emm typed by standard methods. GAS was isolated from 449 (25.5%) of the 1,759 sore throat episodes. Painful cervical adenopathy identified 403 children (89.8%) with GAS infection and was absent in 369 uninfected children (28.2%). Emm type was determined in 396 (88.2%) of the 449 culture-positive children; 70 types were represented and 14 types accounted for 49% of isolates. Based on the proportion of the 449 isolates bearing emm types included in the 30-valent vaccine (31.0%) plus non-vaccine types previously shown to react to vaccine-induced bactericidal antibodies (44.1%), the vaccine could protect against almost 75% of GAS infections among Bamako schoolchildren. Two promising strategies could reduce RHD in low resource settings. Administering antibiotics to children with sore throat and tender cervical adenopathy could treat most GAS-positive children while reducing use of unnecessary antibiotics for uninfected children. Broad coverage against M types associated with pharyngitis in Bamako schoolchildren might be achieved with the 30-valent GAS vaccine under development.
Tropical Medicine & International Health, 2008
objective To study the effectiveness of the Haemophilus influenzae type b (Hib) vaccination progr... more objective To study the effectiveness of the Haemophilus influenzae type b (Hib) vaccination program in Uganda.
PLoS ONE, 2012
Background: Maternal immunization has gained traction as a strategy to diminish maternal and youn... more Background: Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.
PLoS Neglected Tropical Diseases, 2010
Background: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cau... more Background: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) are emerging as a prominent cause of invasive disease (bacteremia and focal infections such as meningitis) in infants and young children. Importantly, including data from Mali, three serovars, Salmonella enterica serovar Typhimurium, Salmonella Enteritidis and Salmonella Dublin, account for the majority of non-typhoidal Salmonella isolated from these patients.
The Pediatric Infectious Disease Journal, 2002
Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of... more Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of a 10-year-old child with influenza B encephalitis and profound weakness who was treated with oseltamivir is presented. This case illustrates several of the unusual findings associated with influenza infections and the result of treatment of influenza B encephalitis with oseltamivir.
The Pediatric Infectious Disease Journal, 2005
Population-based, bacteriologically confirmed disease burden data aid decision makers in African ... more Population-based, bacteriologically confirmed disease burden data aid decision makers in African countries pondering whether to introduce Haemophilus influenzae type b (Hib) immunization for infants. A bacteriology laboratory was established in Hopital Gabriel Toure, serving Bamako, Mali. Children age 0-15 years with fever &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =39 degrees C or syndromes compatible with invasive bacterial disease (meningitis, etc.) were eligible. From 2 to 5 mL of blood or relevant body fluid were inoculated into Bactec Ped Plus/F medium for automated culture; body fluids were also inoculated directly onto solid media. Hib was confirmed by standard microbiologic techniques and antibiograms generated by disk diffusion. From June 1, 2002 to May 31, 2004, 3592 (87.8%) of 4092 children admitted to Hopital Gabriel Toure with high fever or suspected invasive bacterial disease were cultured, including 1745 who were 0-11 months old, 1132 who were 1-4 years old and 715 who were 5-15 years old. Hib was isolated from 207 Bamako children, 81 from blood alone and 124 from cerebrospinal fluid (with or without positive blood culture). Of 207 cases 204 (98.5%) occurred in children younger than age 5 years (annual incidence, 45.2/10) and 159 (77%) in infants age 0-11 months (annual incidence, 158.4/10). Peak incidence (370.0 cases/10) and 12 of 21 Hib deaths occurred in 6- to 7-month-olds. Of the Hib isolates, 11.1% were resistant to ampicillin, 32% to chloramphenicol and 0.5% to ceftriaxone. The substantial burden of invasive Hib disease documented in Bamako has prompted the Malian government to introduce routine infant immunization with Hib conjugate.
The Pediatric Infectious Disease Journal, 2004
Prevention of invasive pneumococcal disease (IPD) in children is a global public health priority,... more Prevention of invasive pneumococcal disease (IPD) in children is a global public health priority, and determination of the most common serotypes is crucial for vaccine development and implementation. We performed prospective surveillance for IPD in hospitalized children in Bamako, Mali. All febrile children and others suspected to have invasive bacterial disease had an admission blood culture and cultures of additional anatomic sites when indicated. Standard microbiologic methods were used to identify, serotype and determine antibiograms for pneumococcal isolates. Of 2,049 children enrolled, 106 (5%) had an IPD, including 47 cases of meningitis and 44 bacteremic pneumonias. The incidence was highest in infants (84/100,000/year). The overall IPD case fatality rate was 24%. Only 2 of 96 isolates were nonsusceptible to penicillin. The serotypes isolated were 5 (54%), 2 (14%), 7F (10%), 19F (8%), 6A/B (3%), 9V (3%), 1 (2%) and 14 (1%). IPD is common and frequently fatal among hospitalized children in Mali, but surprisingly little resistance has occurred. Notably, 91% of the serotypes causing IPD in Bamako children are found in the 11-valent pneumococcal conjugate vaccine.
The Pediatric Infectious Disease Journal, 2006
Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow ... more Serosurveys that measure tetanus antitoxin can complement immunization coverage surveys to allow evaluation of immunization services in developing countries. Measurement of IgG tetanus antitoxin in oral fluid was investigated as a practical and noninvasive alternative to and correlate of serum antibodies. Serum and oral fluid were collected from Malian infants, toddlers and adults (males without a history of tetanus vaccination). Specific IgG tetanus antitoxin was measured by enzyme-linked immunosorbent assay in serum (S-ELISA) and oral fluid (OF-ELISA). One hundred forty-two pairs of serum and oral fluid samples were collected from infants, 35 pairs from toddlers and 35 pairs from adults. IgG tetanus antitoxin titers measured by OF-ELISA were 100-fold lower than those measured by S-ELISA but they correlated strongly (r = 0.90, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). All 35 toddlers who had received 2 or 3 doses of diphtheria-tetanus-pertussis (DTP) vaccine (100%) had serum tetanus antitoxin levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 28 of 35 (80%) had oral fluid values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL. Among adults lacking a history of tetanus immunization, only 6 of 35 (17.1%) had serum titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.15 IU/mL and 4 of 35 (11%) had oral fluid titers &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL in oral fluid. IgG tetanus antitoxin in oral fluid correlates well with levels in serum. OF-ELISA values &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=0.0015 IU/mL constitute protection against tetanus and in subjects &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;12 months of age imply multiple prior contacts with immunization services. IgG tetanus antitoxin measured by OF-ELISA provides a logistically practical alternative for performing seroprevalence surveys.
New England Journal of Medicine, 2011