PubMed Health⌕ Search

Biomedical subjects

Karen L Kotloff

Publications and source records attributed to Karen L Kotloff.

14 recordsLinked to original sources
PubMed2025

Vaccine efficacy of NVX-CoV2373 against SARS-CoV-2 infection in adolescents in the USA: an ancillary study to a phase 3, observer-blinded, randomised, placebo-controlled trial.

BACKGROUND: Although existing COVID-19 vaccines are known to be highly effective against severe disease and death, data are needed to assess their ability to reduce SARS-CoV-2 infection. We aimed to estimate the efficacy of the NVX-CoV2373 protein subunit vaccine against SARS-CoV-2 infection, regardless of symptoms, among adolescents. METHODS: We performed an ancillary observational study (SNIFF) to the phase 3, observer-blinded, randomised, placebo-controlled PREVENT-19 trial that assessed vaccine efficacy against symptomatic COVID-19 in the USA. Participants in the PREVENT-19 trial included healthy adolescents aged 12-17 years and with no history of laboratory-confirmed SARS-CoV-2 infection. They were randomly assigned (2:1) to receive either the NVX-CoV2373 (Novavax, Gaithersburg, MD, USA) vaccine (immediate NVX-CoV2373 group) or placebo (delayed NVX-CoV2373 group) on days 0 and 21 (initial series). After 2 months, in a crossover series, participants received two doses, 21 days apart, of the intervention that they did not receive in their initial series. Participants at 47 of the PREVENT-19 sites were invited to participate in the SNIFF study and self-collect nasal swabs at home twice weekly for SARS-CoV-2 testing to assess vaccine efficacy against SARS-CoV-2 infection. This primary outcome was defined as the first identification of SARS-CoV-2 detected by RT-PCR, regardless of symptoms, with onset within 4 weeks after the second dose of the initial vaccination series until the second dose of the crossover series. Secondary outcomes were vaccine efficacy against asymptomatic and minimally symptomatic SARS-CoV-2 infection, durability of vaccine efficacy against SARS-CoV-2 infection, and durability of vaccine efficacy against asymptomatic and minimally symptomatic infections. Outcomes were analysed in the modified intention-to-treat population, which included all participants without previous SARS-CoV-2 infection and was restricted to participants enrolled within 4 weeks of the second dose of the primary (primary analysis population) or crossover (post-crossover analysis population) series. This study is registered with ClinicalTrials.gov (NCT04611802). FINDINGS: Between June 1 and Dec 17, 2021, 1196 (53·2%) of the 2247 adolescent participants recruited in the PREVENT-19 trial enrolled in the SNIFF study. The primary analysis population included 471 participants in the immediate NVX-CoV2373 group and 220 in the delayed NVX-CoV2373 group. Incidence of SARS-CoV-2 infection was 14·9 cases per 100 person-years (95% CI 7·9-25·5) in the immediate group and 54·2 cases per 100 person-years (33·6-82·9) in the delayed group; vaccine efficacy was 73·5% (95% CI 47·1-86·7; p=0·0002). Incidence of minimally symptomatic or asymptomatic SARS-CoV-2 infection was 10·3 cases per 100 person-years (95% CI 4·7-19·6) in the immediate group and 36·1 cases per 100 person-years (19·8-60·7) in the delayed group; vaccine efficacy was 72·8% (95% CI 37·1-88·2; p=0·0023). After the second crossover dose, incidence of SARS-CoV-2 was 14·6 cases per 100 person-years (95% CI 8·6-23·0) in the immediate group (receiving placebo at crossover) and 9·1 cases per 100 person-years (3·0-21·3) in the delayed group, with a durability ratio of 160·3 (95% CI 59·5-431·6; p=0·35). Almost all infections after crossover were minimally symptomatic or asymptomatic, with a durability ratio of 151·4 (55·9-410·4; p=0·41). INTERPRETATION: Among adolescents participating in the PREVENT-19 trial during the delta (B.1.617.2) variant wave of the COVID-19 pandemic, the NVX-CoV2373 vaccine was highly efficacious against SARS-CoV-2 infection regardless of symptoms, indicating its potential to reduce the reservoir of infections that contribute to community transmission. FUNDING: US Department of Health and Human Services, Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Adolescent↗
PubMed2006

Measurement of tetanus antitoxin in oral fluid: a tool to conduct serosurveys.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Body Fluids↗
PubMed2005

Burden of invasive disease caused by Haemophilus influenzae type b in Bamako, Mali: impetus for routine infant immunization with conjugate vaccine.

BACKGROUND: 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. METHODS: A bacteriology laboratory was established in Hopital Gabriel Toure, serving Bamako, Mali. Children age 0-15 years with fever > 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. RESULTS: 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. CONCLUSIONS: The substantial burden of invasive Hib disease documented in Bamako has prompted the Malian government to introduce routine infant immunization with Hib conjugate.

Adolescent↗
PubMed2005

Clinical and microbiological responses of volunteers to combined intranasal and oral inoculation with a Streptococcus gordonii carrier strain intended for future use as a group A streptococcus vaccine.

Streptococcus gordonii shows promise as a live mucosal vaccine vector for immunization against respiratory pathogens. In preparation for clinical trials to evaluate S. gordonii engineered to express group A streptococcal M protein antigens, we characterized the responses of 150 healthy volunteers to combined nasal and oral inoculation with approximately 1.5 x 10(9) CFU of SP204(1-1), an S. gordonii strain not bearing vaccine antigens. SP204(1-1) was selected for resistance to streptomycin and 5-fluoro-2-deoxyuridine to distinguish it from indigenous flora. In two antibiotic treatment studies, we performed serial culturing of nose, mouth, and saliva samples from 120 subjects treated with azithromycin beginning 5 days after inoculation to determine whether SP204(1-1) could be rapidly eliminated should safety concerns arise. A natural history study was performed to assess the time until spontaneous eradication in the remaining 30 subjects, who did not receive the antibiotic and who were monitored with repeated culturing for 14 weeks after inoculation. SP204(1-1) was generally well tolerated. Symptoms reported most often within 5 days of inoculation were nasal congestion (36%), headache (30%), and sore throat (19%). The strain was detected by culturing in 98% of subjects. A single dose of azithromycin eliminated colonization in 95% of subjects; all subjects receiving a 5-day course of an antibiotic showed clearance by day 11. Without the antibiotic, 82% of subjects showed spontaneous eradication of the implanted strain within 7 days, and all showed clearance by 35 days. The results of these clinical trials provide encouragement that the use of S. gordonii as a live mucosal vaccine vector is a feasible strategy.

Administration, Intranasal↗
PubMed2004

Deletion in the Shigella enterotoxin genes further attenuates Shigella flexneri 2a bearing guanine auxotrophy in a phase 1 trial of CVD 1204 and CVD 1208.

BACKGROUND: We created a live, attenuated, oral Shigella vaccine by constructing a lineage of guanine auxotrophs and conducted a double-blind, placebo-controlled trial to ascertain (1) the attenuation profile of Delta guaBA Shigella flexneri 2a, which harbors deletions in the guanine nucleotide synthesis pathway (CVD 1204); (2) additional attenuation conferred by deletions in set and sen genes encoding Shigella enterotoxins (ShETs) 1 and 2, respectively (CVD 1208); and (3) the relative immunogenicity of these constructs. METHODS: Inpatient volunteers received a single oral dose of CVD 1204, CVD 1208 (10(7), 10(8), or 10(9) cfu), or placebo. Clinical, immunologic, and microbiologic responses were evaluated. RESULTS: Reactogenicity occurred in 8 of 23 recipients of CVD 1204, characterized by diarrhea (30%), fever (22%), and/or dysentery (17%), but in only 1 (5%) of 21 recipients of CVD 1208 (brief fever) (P=.02, Fisher's exact test). Antilipopolysaccharide responses, as measured by antibody-secreting cell, serum, or fecal antibody levels, occurred in 67%, 71%, and 100% of recipients of CVD 1204 and in 86%, 43%, and 100% of recipients of CVD 1208 at doses of 10(7), 10(8), and 10(9) cfu, respectively. CONCLUSIONS: We conclude that 1 or both ShETs are virulence determinants in humans; their inactivation, in combination with Delta guaBA, leads to a well-tolerated and immunogenic Shigella vaccine candidate.

Administration, Oral↗
PubMed2004

Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial.

CONTEXT: Group A streptococcal infections and their sequelae represent a global health problem. Recent advances have allowed previous obstacles associated with group A streptococcal vaccine development to be overcome. OBJECTIVE: To preliminarily evaluate the safety and immunogenicity of ascending doses of a recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 in healthy volunteers. DESIGN, SETTING, AND PARTICIPANTS: An open-label, uncontrolled, dose-ascending phase 1 vaccine trial of 28 healthy adult volunteers aged 18 to 50 years recruited from the metropolitan area of Baltimore, Md, between October 5, 1999, and February 26, 2003, using newspaper advertisements and posted fliers, and evaluated in the outpatient facility of the Center for Vaccine Development. INTERVENTIONS: Each volunteer received 3 spaced intramuscular injections of 50 microg (n = 8), 100 micro g (n = 10), or 200 microg (n = 10) of hexavalent group A streptococcal vaccine formulated with aluminum hydroxide into the deltoid muscle of alternating arms. MAIN OUTCOME MEASURES: Assessments of clinical safety, including elicitation of antibodies that cross-react with host tissues, and immunogenicity as measured by enzyme-linked immunosorbent assay (ELISA) and assays of opsonophagocytic- and bactericidal-antibody responses. RESULTS: One year of intensive follow-up revealed the vaccine to be well tolerated. There was no evidence of tissue cross-reactive antibodies or immunological complications. At the highest (200 microg) dose, vaccination elicited significant increases in geometric mean antibody levels to all 6 component M antigens by ELISA (all P<.01) and to 5 of 6 M types in the opsonophagocytosis assay (all P<.05). In addition, postvaccination increases in serum bactericidal activity of at least 30% were observed in 31 (55%) of 56 assays. CONCLUSION: These results provide the first evidence in humans that a hybrid fusion protein is a feasible strategy for evoking type-specific opsonic antibodies against multiple serotypes of group A streptococcus without eliciting antibodies that cross-react with host tissues, which represents a critical step in the development of a vaccine.

Adult↗
PubMed2004

The causes of hospital admission and death among children in Bamako, Mali.

The health burden and mortality caused by infections during childhood remain large in sub-Saharan Africa. We performed a review of the causes of hospitalization and death among children admitted to a pediatric teaching hospital in Bamako, Mali. Medical records of children admitted throughout 2000 were systematically sampled and abstracted for demographics, diagnosis, hospital course, and disposition. A sample of 1644 charts, from 5001 admitted children, were abstracted. The median age was 8 months. Half of the children had a febrile illness. All diagnoses were made clinically. The annual incidence per 100,000 and case fatality rates of the four most common serious infections, excluding malaria, were as follows: pneumonia, 165 (12 per cent); sepsis, 75 (37 per cent); meningitis, 71 (20 per cent); and enteric fever, 14 (12 per cent). An estimated 1300 children were admitted with thick-smear confirmed malaria; at least 64 per cent met World Health Organization criteria for severe malaria and 11 per cent died. Seventy-one per cent of admissions were due to infections. Overall 21 per cent of children admitted died in the hospital, most within the first 3 days of admission. Infectious diseases remain the primary cause of hospitalization among Malian children and frequently lead to death. A substantial proportion of this morbidity and mortality is probably attributable to vaccine-preventable diseases, such as Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis. Prospective surveillance using microbiological data is needed to delineate the organism-specific burdens.

Adolescent↗
PubMed2004

Invasive pneumococcal infections among hospitalized children in Bamako, Mali.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Adolescent↗
PubMed2003

B cell responses in gastric antrum and duodenum following oral inactivated Helicobacter pylori whole cell (HWC) vaccine and LT(R192G) in H pylori seronegative individuals.

To investigate whether B cell-specific responses could be elicited in the gastric mucosa of Helicobacter pylori (HP) naive subjects, five volunteers ingested three doses of a HP killed whole cell (HWC) vaccine with 25 microg of recombinant heat-labile toxin (LT(R192G)). Two of three subjects had detectable LT(R192G) and HWC IgA antibody secreting cell (ASC) gastric responses. LT(R192G) and HWC responses in duodenal were 5-14-fold higher than those detected in antral biopsies (P<0.01 and P=0.05, respectively). These results provide the first evidence that specific gastric B cell responses can be induced in HP-non-infected individuals following oral immunization.

Adult↗
PubMed2003

Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A.

There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine to protect high-risk individuals against C. difficile-associated diarrhea and colitis.

Adult↗
PubMed2003

Human challenge studies with infectious agents.

Experimental inoculation of healthy volunteers with infectious agents has been practiced by investigators for many years to elucidate mechanisms of microbial virulence, disease pathogenesis, host immunity, and vaccine efficacy. Establishing these models requires detailed attention to scientific, ethical, and medical principles to ensure the safety of the participants and their community contacts and to generate valid observations that can be generalized to natural infections. This discussion provides examples of the potential values and applications of human challenge studies, addresses issues that must be considered in establishing a new challenge model, and examines the limitations of human data generated in this experimental setting.

Ethics, Medical↗
PubMed2002

Phase I evaluation of delta virG Shigella sonnei live, attenuated, oral vaccine strain WRSS1 in healthy adults.

We conducted a phase I trial with healthy adults to evaluate WRSS1, a live, oral Delta virG Shigella sonnei vaccine candidate. In a double-blind, randomized, dose-escalating fashion, inpatient volunteers received a single dose of either placebo (n = 7) or vaccine (n = 27) at 3 x 10(3) CFU (group 1), 3 x 10(4) CFU (group 2), 3 x 10(5) CFU (group 3), or 3 x 10(6) CFU (group 4). The vaccine was generally well tolerated, although a low-grade fever or mild diarrhea occurred in six (22%) of the vaccine recipients. WRSS1 was recovered from the stools of 50 to 100% of the vaccinees in each group. The geometric mean peak anti-lipopolysaccharide responses in groups 1 to 4, respectively, were 99, 39, 278, and 233 for immunoglobulin (IgA) antibody-secreting cell counts; 401, 201, 533, and 284 for serum reciprocal IgG titers; and 25, 3, 489, and 1,092 for fecal IgA reciprocal titers. Postvaccination increases in gamma interferon production in response to Shigella antigens occurred in some volunteers. We conclude that WRSS1 vaccine is remarkably immunogenic in doses ranging from 10(3) to 10(6) CFU but elicits clinical reactions that must be assessed in further volunteer trials.

Administration, Oral↗