Typhoid Vaccine Research Articles

Discovery of New States of Immunomodulation for Vaccine Adjuvants via High Throughput Screening: Expanding Innate Responses to PRRs.

Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This is often achieved through adjuvants, molecules that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Here, we demonstrate the ability to alter and improve adjuvant activity via the addition of small molecule "immunomodulators". By modulating signaling activity instead of receptor binding, these molecules allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates of a protective immune responses in a commercial flu vaccine model and reduced correlates of reactogenicity in a typhoid vaccine model. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy.

Indian Essential Medicine List for Children: Time to Revisit.

The majority of the under five mortality rate (U5MR) in India were due to treatable causes and could have been prevented by providing quality medicines. Availability and affordability of medicine can be improved by the introduction of essential medicine concepts. The current study was carried out to compare the latest edition of the WHO essential medicine list for children (EMLc) with that of Indian EMLc to determine the need to update the Indian EMLc. A descriptive observational study was carried out in the Department of Pharmacology of a tertiary care hospital. The latest edition of WHO EMLc (8th) was compared with the latest edition of Indian EMLc (1st) in terms of inclusion of categories or subcategories, the number of medicines in each category or subcategories, medicines which are present in WHO EMLc but missing in Indian EMLc and vice versa. In total 134 medicines are present in Indian EMLc as compared to 350 medicines in WHO EMLc. The important categories which are completely missing in Indian EMLc are medicines for reproductive health and perinatal care, peritoneal dialysis solution, medicines for mental and behavioral disorders, and medicines for diseases of joints. The important medicines which are not included in Indian EMLc are bedaquilline, delaminid, cefixime, piperacillin+tazobactum, vancomycin, acyclovir, azathioprine, cisplatin, and filgrastim. Important vaccines including rotavirus, cholera, hepatitis, and typhoid vaccine are not mentioned in Indian EMLc. There is an urgent need to update the Indian EMLc in order to promote access to pediatric medicine and facilitate the rational use of medicines.

Typhoid Fever Surveillance, Incidence Estimates, and Progress Toward Typhoid Conjugate Vaccine Introduction - Worldwide, 2018-2022.

Typhoid fever, an acute febrile illness caused by Salmonella enterica serovar Typhi (S. Typhi), is endemic in many low- and middle-income countries† (1). In 2015, an estimated 11-21 million typhoid fever cases and 148,000-161,000 associated deaths occurred worldwide (2). Effective prevention strategies include improved access to and use of infrastructure supporting safe water, sanitation, and hygiene (WASH); health education; and vaccination (1). The World Health Organization (WHO) recommends programmatic use of typhoid conjugate vaccines for typhoid fever control and prioritization of vaccine introduction in countries with the highest typhoid fever incidence or high prevalence of antimicrobial-resistant S. Typhi (1). This report describes typhoid fever surveillance, incidence estimates, and the status of typhoid conjugate vaccine introduction during 2018-2022. Because routine surveillance for typhoid fever has low sensitivity, population-based studies have guided estimates of case counts and incidence in 10 countries since 2016 (3-6). In 2019, an updated modeling study estimated that 9.2 million (95% CI = 5.9-14.1) typhoid fever cases and 110,000 (95% CI = 53,000-191,000) deaths occurred worldwide, with the highest estimated incidence in the WHO South-East Asian (306 cases per 100,000 persons), Eastern Mediterranean (187), and African (111) regions (7). Since 2018, five countries (Liberia, Nepal, Pakistan, Samoa [based on self-assessment], and Zimbabwe) with estimated high typhoid fever incidence (≥100 cases per 100,000 population per year) (8), high antimicrobial resistance prevalence, or recent outbreaks introduced typhoid conjugate vaccines into their routine immunization programs (2). To guide vaccine introduction decisions, countries should consider all available information, including surveillance of laboratory-confirmed cases, population-based and modeling studies, and outbreak reports. Establishing and strengthening typhoid fever surveillance will be important to measure vaccine impact.

Comparative frequency of specified adverse events following Vero cell culture-derived Japanese encephalitis and Vi capsular polysaccharide typhoid vaccines in U.S. military personnel, July 2011-August 2019.

Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC; Ixiaro) was approved in the United States in 2009. The previous JE vaccine, an inactivated mouse brain-derived vaccine, had been associated with rare, but serious, allergic and neurologic adverse events (AE). Studies and AE surveillance have supported JE-VC's safety, but one evaluation among military personnel found elevated hypersensitivity and neurologic AE rates. However, co-administration of multiple vaccines to some personnel might have affected results. We retrospectively compared rates of hypersensitivity and neurologic AEs within 28days following vaccination of military personnel with JE-VC or parenteral Vi capsular polysaccharide typhoid vaccine administered without other vaccines from July 1, 2011, through August 31, 2019. Rates of most events were similar between the vaccines. Only delayed hypersensitivity reactions occurred more frequently following JE-VC (rate ratio: 4.2, 95% CI 1.2-15.3; p=0.03), but rates were low for both vaccines. These results support JE-VC's safety.

Estimates of the cost to build a stand-alone environmental surveillance system for typhoid in low- and middle-income countries.

The typhoid conjugate vaccine is a safe and effective method for preventing Salmonella enterica serovar Typhi (typhoid) and the WHO's guidance supports its use in locations with ongoing transmission. However, many countries lack a robust clinical surveillance system, making it challenging to determine where to use the vaccine. Environmental surveillance is one alternative approach to identify ongoing transmission, but the cost to implement such a strategy is previously unknown. This paper estimated the cost of setting up and operating an environmental surveillance program for thirteen protocols that are in development, including thirteen cost components and twenty-seven pieces of equipment. Unit costs were obtained from research labs involved in protocol development and equipment information was obtained from manufacturers and the expert opinion of individuals in participating labs. We used Monte Carlo simulations to estimate the costs and the input parameters were modeled as distributions to incorporate the uncertainty. Total costs per sample including setup, overhead, and operational costs, range from $357-794 at a scale of 25 sites to $116-532 at 125 sites. Operational costs (ongoing expenditures) range from $218-584 per sample at a scale of 25 sites to $74-421 at 125 sites. Eleven of the thirteen protocols have operational costs below $200, at this higher scale. Protocols with higher up-front equipment costs benefit more from scale efficiencies and sensitivity analyses show that laboratory labor, processes, and consumables are the primary drivers of uncertainty. At scale, environmental surveillance for typhoid may be affordable (depending on the protocol, scale, and geographic context), though cost will need to be considered alongside future evaluations of test sensitivity. Opportunities to leverage existing infrastructure and multi-disease platforms may be necessary to further reduce costs.

Environmental surveillance for Salmonella Typhi as a tool to estimate the incidence of typhoid fever in low-income populations.

Background: The World Health Organisation recommends prioritised use of recently prequalified typhoid conjugate vaccines in countries with the highest incidence of typhoid fever. However, representative typhoid surveillance data are lacking in many low-income countries because of the costs and challenges of diagnostic clinical microbiology. Environmental surveillance (ES) of Salmonella Typhi in sewage and wastewater using molecular methods may offer a low-cost alternative, but its performance in comparison with clinical surveillance has not been assessed. Methods: We developed a harmonised protocol for typhoid ES and its implementation in communities in India and Malawi where it will be compared with findings from hospital-based surveillance for typhoid fever. The protocol includes methods for ES site selection based on geospatial analysis, grab and trap sample collection at sewage and wastewater sites, and laboratory methods for sample processing, concentration and quantitative polymerase chain reaction (PCR) to detect Salmonella Typhi. The optimal locations for ES sites based on digital elevation models and mapping of sewage and river networks are described for each community and their suitability confirmed through field investigation. We will compare the prevalence and abundance of Salmonella Typhi in ES samples collected each month over a 12-month period to the incidence of blood culture confirmed typhoid cases recorded at referral hospitals serving the study areas. Conclusions: If environmental detection of Salmonella Typhi correlates with the incidence of typhoid fever estimated through clinical surveillance, typhoid ES may be a powerful and low-cost tool to estimate the local burden of typhoid fever and support the introduction of typhoid conjugate vaccines. Typhoid ES could also allow the impact of vaccination to be assessed and rapidly identify circulation of drug resistant strains.

Delivery cost of the first public sector introduction of typhoid conjugate vaccine in Navi Mumbai, India.

Navi Mumbai Municipal Corporation (NMMC), a local government in Mumbai, India, implemented the first public sector TCV campaign in 2018. This study estimated the delivery costs of this TCV campaign using a Microsoft Excel-based tool based on a micro-costing approach from the government (NMMC) perspective. The campaign's financial (direct expenditures) and economic costs (financial costs plus the monetized value of additional donated or existing items) incremental to the existing immunization program were collected. The data collection methods involved consultations with NMMC staff, reviews of financial and programmatic records of NMMC and the World Health Organization (WHO), and interviews with the health staff of sampled urban health posts (UHPs). Three UHPs were purposively sampled, representing the three dominant residence types in the catchment area: high-rise, slum, and mixed (high-rise and slum) areas. The high-rise area UHP had lower vaccination coverage (47%) compared with the mixed area (71%) and slum area UHPs (76%). The financial cost of vaccine and vaccination supplies (syringes, safety boxes) was $1.87 per dose, and the economic cost was $2.96 per dose in 2018 US dollars. Excluding the vaccine and vaccination supplies cost, the financial delivery cost across the 3 UHPs ranged from $0.37 to $0.53 per dose, and the economic delivery cost ranged from $1.37 to $3.98 per dose, with the highest delivery costs per dose in the high-rise areas. Across all 11 UHPs included in the campaign, the weighted average financial delivery cost was $0.38 per dose, and the economic delivery cost was $1.49 per dose. WHO has recommended the programmatic use of TCV in typhoid-endemic countries, and Gavi has included TCV in its vaccine portfolio. This first costing study of large-scale TCV introduction within a public sector immunization program provides empirical evidence for policymakers, stakeholders, and future vaccine campaign planning.

A randomized, observer-blind, controlled phase III clinical trial assessing safety and immunological non-inferiority of Vi-diphtheria toxoid versus Vi-tetanus toxoid typhoid conjugate vaccine in healthy volunteers in eastern Nepal

ABSTRACT Typhoid remains one of the major serious health concerns for children in developing countries. With extremely drug-resistant cases emerging, preventative measures like sanitation and vaccination, including typhoid conjugate vaccines (TCV) remain the mainstay in its prevention and control. Different types of TCVs are being developed to meet the global demand. This report outlines the results from a study done to assess the immunogenicity and safety of Vi-Diphtheria toxoid (Vi-DT) TCV in Nepal. The study was a randomized, active-controlled, immunological non-inferiority and safety study. Eligible participants from Sunsari and Morang districts of eastern Nepal were randomized into 4 study groups (A-D) within 3 age strata (6 months to <2 years, 2 to <18 years, and 18 to 45 years). Groups A to C received a single dose (25 μg) of Vi-DT test vaccine from any of the 3 lots, while group D received the comparator, Typbar-TCV®, Vi-tetanus toxoid (Vi-TT) vaccine (25 μg) in 1:1:1:1 ratio and evaluated at 4 weeks postvaccination with 6 months follow-up. Amongst 400 randomized participants, anti-Vi-IgG seroconversion rates for all age strata in Vi-DT pooled groups (A+B+C) were 100.00% (97.5% CI 98.34–100.00) vs 98.99% (97.5% CI 93.99–99.85) in Vi-TT group (D) at 4 weeks. Comparable safety events were reported between the groups. Three serious adverse events (1 in Vi-DT; 2 in Vi-TT group) were reported during the 6 months follow-up, none being related to the investigational product. Thus, Vi-DT vaccine is safe, immunogenic, and immunologically non-inferior to Vi-TT when analyzed at 4 weeks postvaccination.

Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness.

Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9months of age, and routine vaccination at 9months with a one-time catch-up campaign (ages 9months to 15years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46% over a 10-year time horizon under an optimistic scenario (95% initial vaccine efficacy and 19-year mean duration of protection), and by 2-16% under a pessimistic scenario (82% initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90% and 6-35% in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.

New typhoid vaccine using sponge-like reduced protocol: development and evaluation.

Typhoid remains a major health problem, especially in the developing world. Furthermore, the emergence of multidrug-resistant and extensively drug-resistant strains of Salmonella typhi added a sense of urgency to develop more effective typhoid vaccines, one of which is bacterial ghosts (BGs), prepared by both genetic and chemical means. The chemical method includes incubation with numerous agents for a short time at their minimum inhibitory or minimum growth concentrations. This study included the preparation of BGs by a sponge-like reduced protocol (SLRP). Critical concentrations of sodium dodecyl sulfate, NaOH, and H2O2 were used. Moreover, high-quality BGs were visualized by scanning electron microscope (SEM). Subculturing was used to confirm the absence of vital cells. Besides, the concentrations of the released DNA and protein were estimated spectrophotometrically. In addition, the integrity of cells was proved by visualizing Gram-stained cells using a light microscope. Furthermore, a comparison between the immunogenicity and safety of the prepared vaccine and the available whole-cell killed vaccine was established. Improved preparation of high-quality BGs of S. typhi, visualized by SEM, revealed punctured cells with intact outer shells. Moreover, the absence of vital cells was confirmed by subculturing. At the same time, the release of respective amounts of proteins and DNA is another evidence of BGs' production. Additionally, the challenge test provided evidence that the prepared BGs are immunogenic and have the same efficacy as the whole cell vaccine. The SLRP provided a simple, economical, and feasible method for BGs preparation.

Financial burden on the parents of children infected with extensively drug resistant Salmonella infection

Background: Typhoid illness is a significant cause of morbidity in Pakistan. This study aimed to determine the financial burden on parents of children infected with extensively drug-resistant (XDR) salmonella infection.&#x0D; Patients and methods: This observational study included 159 patients aged 6 months to 13 years admitted through OPD/ER of Karachi Adventist Hospital with the diagnosis of enteric fever and intravenous antibiotics started as per local antibiogram. To remove recall bias antibiotic cost before hospitalization was not included. All those patients who were culture positive for XDR salmonella, either continued or shifted to newer antibiotics as per susceptibility pattern were included. Depending upon the type and duration of antibiotic therapy cost was calculated in Pakistani rupee (1 USD = ~225 PKR).&#x0D; Results: Total 60.4% of patients aged less than 7.5 years; 62.3% were male, 41.5% from urban areas, 15.1% had graduated mothers, 27% had graduated fathers, 5.7% uses boiled water, and 1.9% typhoid vaccination. In 54.1% of patients antibiotic cost reached &gt;40k PKR. Patients with urban dwelling were 0.29 times less likely for higher cost, increase in duration of fever (&gt;7 days) at admission increased the cost 5.73 times, XDR samples found 13.5 time more likely for higher cost, and TLC between 4000 – 11000/mm3 gave negative association with higher cost.&#x0D; Conclusion: The burden of XDR salmonella infection is heavy and is related to urban residence, duration of fever at admission, and length of hospital stay.

Safety, immunogenicity and non-interference of concomitant Typhoid Vi capsular polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV®) and measles or measles-mumps-rubella vaccines in 8–9 months-old Indian children

ABSTRACT We evaluated safety, reactogenicity, and immunogenicity when the WHO-prequalified single-dose Typhoid Vi-polysaccharide conjugate vaccine, Typbar-TCV®, was administered concomitantly with measles (MV) or measles-mumps-rubella (MMR) vaccines in 8- or 9-month-old children. We enrolled 493 children who were randomized 2:1:1:1 to four groups to receive either TCV (0.5 mL intramuscularly) and MV (0.5 ml subcutaneously) concomitantly at 9 months of age (Group 1) with two subgroups given TCV booster 28 days (Group 1A) or 180 days (Group 1B) later, or MV on Day 0 and TCV on Day 28 (Group 2); or TCV at 8 months of age and MV 28 days later (Group 3), or MV only at 9 months of age (Group 4). All children received MMR at 15 months of age. We observed no statistically significant differences between group rates of solicited or unsolicited adverse events assessed throughout the study. Seroconversion rates for measles, mumps, and rubella antibodies were unaffected by concomitant administration with TCV, being similar in Groups 1, 2, and 3 and comparable to Group 4 (Control). IgG anti-Vi antibody titers were similar in all groups after primary Typbar-TCV® vaccination and were not increased by a second dose 28 days later. A small response to a booster dose of Typbar-TCV® given at 180 days did not achieve the high titers observed after the first dose, suggesting that booster vaccination may be more effective after a longer interval than 6 months. Typbar-TCV® can be safely co-administered with measles and MMR vaccines in children aged ≥9 months. Clinical trial registration number: CTRI/2014/04/004532.

Typhoid conjugate vaccine effectiveness in Malawi: evaluation of a test-negative design using randomised, controlled clinical trial data

Typhoid conjugate vaccines are being introduced in low-income and middle-income countries to prevent typhoid illness in children. Vaccine effectiveness studies assess vaccine performance after introduction. The test-negative design is a commonly used method to estimate vaccine effectiveness that has not been applied to typhoid vaccines because of concerns over blood culture insensitivity. The overall aim of the study was to evaluate the appropriateness of using a test-negative design to assess typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine (Vi-TT) effectiveness using a gold standard randomised controlled trial database. Using blood culture data from a randomised controlled trial of Vi-TT in Malawi, we simulated a test-negative design to derive vaccine effectiveness estimates using three different approaches and compared these to randomised trial efficacy results. In the randomised trial, 27 882 children aged 9 months to 12 years were randomly assigned (1:1) to receive a single dose of Vi-TT or meningococcal capsular group A conjugate vaccine between Feb 21 and Sept 27, 2018, and were followed up for blood culture-confirmed typhoid fever until Sept 30, 2021. For all three test-negative design approaches, vaccine effectiveness estimates (test-negative design A, 80·3% [95% CI 66·2 to 88·5] vs test-negative design B, 80·5% [66·5 to 88·6] vs test-negative design C, 80·4% [66·9 to 88·4]) were almost identical to the randomised trial results (80·4% [95% CI 66·4 to 88·5]). Receipt of Vi-TT did not affect the risk of non-typhoid fever (vaccine efficacy against non-typhoid fever -0·4% [95% CI -4·9 to 3·9] vs -1% [-5·6 to 3·3] vs -2·5% [-6·4 to 1·3] for test-negative design A, test-negative design B, and test-negative design C, respectively). This study validates the test-negative design core assumption for typhoid vaccine effectiveness estimation and shows the accuracy and precision of the estimates compared with the randomised controlled trial. These results show that the test-negative design is suitable for assessing typhoid conjugate vaccine effectiveness in post-introduction studies using blood culture surveillance. Bill & Melinda Gates Foundation.

Cost effectiveness analysis of typhoid fever vaccination in an endemic district of Kabale, Uganda

Background: Typhoid fever is a preventable disease that affects the livelihood security of households and communities, accounting for a significant portion of the disease burden in Kabale district. Various preventive programs to control this burden such as curative services and vaccination are being implemented without empirical evidence of the effectiveness of either program in terms of costs and outcomes.Methodology: The study design is a mixed methods design in which for specific research objectives a cross-sectional survey was carried out in addition to a retrospective costing analysis. The outcome being a cost effectiveness evaluation of vaccination against typhoid with the comparator being no vaccination, expressed as the incremental cost effectiveness ratio. Results: Incidence rate of 39.8 per 1000, a case fatality rate of 0.061, and cost of illness of $75.62 for inpatient care and $33.85 for an outpatient case, with an average cost of illness of typhoid fever in Kabale district to be $54.74. In addition, typhoid fever costs Kabale district $217,158.8, of which $119,814.92 could be saved if a typhoid fever vaccination program is carried out, that will avert 2,189 cases of typhoid every year for three years. Vaccination results in 28,428.32 DALYs avoided. The resulting ICER of -6.348 reveals that the vaccination program against typhoid fever is both extremely cheaper and very effective in averting both typhoid cases and costs.Conclusions: a one-time fixed-post typhoid vaccination campaign in Kabale District, Uganda, was estimated to be a very highly cost-effective intervention from the public sector health care delivery perspective.

Typhoid vaccine does not impact feelings of social connection or social behavior in a randomized crossover trial among middle-aged female breast cancer survivors

BackgroundInflammation can have social consequences, which may be relevant to inflammation’s link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior. MethodIn two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination. ResultsThe typhoid vaccine triggered rises in both inflammatory markers (ps < 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps > 0.64) or performance on explicit (ps > 0.73) or implicit (ps > 0.88) social avoidance tasks. ConclusionMilder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.

Fourier transform infrared spectroscopy (FTIR) analysis, antioxidant and anti-inflammatory activities of leaf and fruit extracts of Gymnosporia montana

Gymnosporia montana, an ethnomedicinal plant from the Celastraceae family, is known as “VIKALO” in Gujarat, which means jaundice curing. In Gujarat's tribal areas, young Vikalo leaves are gnawed to heal jaundice. The main goal of the current study was to perform a pharmacognostical assessment, which included secondary metabolite phytochemical analysis, antioxidant potential analysis, and anti-inflammatory activity assessment of leaf and fruit extracts. Methanolic extraction of shade-dried leaves and fruits was followed by phytochemical studies of secondary metabolites, fractionation of the initial extracts, and FTIR analysis confirmation of a particular category of compounds with their functional groups. Additionally, the potential for anti-inflammatory effects and antioxidant activity of crude extracts were evaluated using DPPH and hydrogen peroxide scavenging techniques. The presence of phytoconstituents like flavonoids, alkaloids, and terpenoids was detected through phytochemical screening. Utilizing Perkin Elmer Spectrum Version 10.03.09, the FT-IR spectra of active classes of compoundsfrom leaf and fruit extracts were assessed. The antioxidant activity of an extract that has been dose-dependently enriched with flavonoid content is significantly increased in comparison to extracts enriched with alkaloids and terpenoids. All methanolic extracts were tested for anti-inflammatory activity against the standard Typhoid vaccine (25 µg/ml, 10 µl) at varying concentrations, and the results were compared to the standard. Again, the crude extracts' flavonoid-enriched fraction demonstrated a discernible decrease in antigen-specific proliferation when contrasted with the control, but no discernible effects were seen with the terpenoid and alkaloid fractions. Ultimately, this study suggests that the flavonoid-rich fraction of methanolic extract has strong anti-inflammatory and antioxidant properties.

Immune non-interference and safety study of Vi-DT typhoid conjugate vaccine with a measles, mumps and rubella containing vaccine in 9–15 months old Nepalese infants

BackgroundTyphoid fever is a common disease in developing countries especially in the Indian subcontinent and Africa. The available typhoid conjugate vaccines (TCV) have been found to be highly immunogenic in infants and children less than 2 years of age. Many countries are planning to adopt TCV in their routine EPI programs around 9 months of age when measles containing vaccines are given. Therefore, Vi-DT TCV was tested in 9–15 months aged healthy infants in Nepal to demonstrate non-interference with a measles containing vaccine. MethodsThis was a randomized, open label, phase III study to assess the immune non-interference, safety, and reactogenicity of Vi-DT typhoid conjugate vaccine when given concomitantly with measles, mumps and rubella (MMR) vaccine. A total of 360 participants aged 9–15 months were enrolled and randomized equally into Vi-DT + MMR (180 participants) or MMR alone (180 participants) group and were evaluated for immunogenicity and safety 28 days post vaccination. ResultsUsing the immunogenicity set, difference between proportions (95% CI) of the Vi-DT + MMR group vs MMR alone group were −2.73% (-8.85, 3.38), −3.19% (-11.25, 4.88) and 2.91% (-3.36, 9.18) for sero-positivity rate of anti-measles, anti-mumps and anti- rubella, respectively. Only the lower bound of the range in difference of the proportions for sero-positivity rate of anti-mumps did not satisfy the non-inferiority criteria as it was above the −10% limit, which may not be of clinical significance. These results were confirmed in the per protocol set. There were no safety concerns reported from the study and both Vi-DT + MMR and MMR alone groups were comparable in terms of solicited and unsolicited adverse events . ConclusionsResults indicated that there is non-interference of MMR vaccine with Vi-DT and Vi-DT conjugate vaccine could be considered as an addition to the EPI schedule among children at risk of contracting typhoid.

Travelers and travel vaccines at six health care systems in the Vaccine Safety Datalink

BackgroundStudying the safety of travel vaccines poses challenges since recipients may be traveling during the risk window for adverse events and the identification of a suitable comparison group can also be difficult. The examination of traveler characteristics, travel vaccination patterns, and health care utilization using electronic health record (EHR) data can inform the feasibility of future travel vaccine safety studies. MethodsA retrospective cohort study of health plan members in the Vaccine Safety Datalink Project aged 9 months and older who had a travel-related encounter or received a travel vaccine from 2009 to 2018 was performed. Travel regions visited, travel duration, type of travel vaccine received (typhoid, yellow fever, Japanese encephalitis, rabies, and cholera), and timing of vaccination date before departure date were described. Sociodemographic information, clinical characteristics, and health care utilization were compared between travelers who received travel vaccines and travelers who did not. ResultsA total of 1,026,822 unique travelers departing from the United States were identified; 612,795 travelers received 898,196 doses of travel vaccines. The most commonly administered travel vaccine was typhoid vaccine and 77% of all travel vaccines were given more than one week prior to departure. Compared with travelers without travel vaccines, travelers with travel vaccines were overall similar but as a group were slightly younger, healthier, and had lower Hispanic representation. Health care utilization dramatically decreased during travel. Outpatient visits decreased from 294.8 visits per 10,000 person-days before travel to 24.2 visits per 10,000 person-days during reported travel dates. ConclusionsThrough the EHR information from almost a million travelers, a departure date and duration of travel were successfully captured for the majority of travelers with corresponding health care utilization data. Time after vaccination and prior to departure can potentially be used in the future to compare travelers who receive travel vaccines with travelers who do not receive travel vaccines when looking at adverse events of interest after vaccination.

Typhoid fever control in the 21st century: where are we now?

Momentum for achieving widespread control of typhoid fever has been growing over the past decade. Typhoid conjugate vaccines represent a potentially effective tool to reduce the burden of disease in the foreseeable future and new data have recently emerged to better frame their use-case. We describe how antibiotic resistance continues to pose a major challenge in the treatment of typhoid fever, as exemplified by the emergence of azithromycin resistance and the spread of Salmonella Typhi strains resistant to third-generation cephalosporins. We review efficacy and effectiveness data for TCVs, which have been shown to have high-level efficacy (≥80%) against typhoid fever in diverse field settings. Data from randomized controlled trials and observational studies of TCVs are reviewed herein. Finally, we review data from multicountry blood culture surveillance studies that have provided granular insights into typhoid fever epidemiology. These data are becoming increasingly important as countries decide how best to introduce TCVs into routine immunization schedules and determine the optimal delivery strategy. Continued advocacy is needed to address the ongoing challenge of typhoid fever to improve child health and tackle the rising challenge of antimicrobial resistance.

Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial

SummaryBackgroundTyphoid fever is a substantial public health problem in Africa, yet there are few clinical trials of typhoid conjugate vaccine (TCV). We assessed immunogenicity and safety of Typbar TCV in Malawi.MethodsThis substudy was nested within a phase 3, double-blind, parallel design, randomised controlled trial of TCV in children from Ndirande Health Centre in Ndirande township, Blantyre, Malawi. To be eligible, participants had to be aged between 9 months and 12 years with no known immunosuppression or chronic health conditions, including HIV or severe malnutrition; eligible participants were enrolled into three strata of approximately 200 children (9–11 months, 1–5 years, and 6–12 years), randomly assigned (1:1) to receive TCV or control (meningococcal serogroup A conjugate vaccine [MCV-A]) intramuscularly. Serum was collected before vaccination and at 28 days and 730–1035 days after vaccination to measure anti-Vi antibodies by ELISA. Because of COVID-19, day 730 visits were extended up to 1035 days. This nested substudy evaluated reactogenicity, safety, and immunogenicity by age stratum. Safety outcomes, analysed in the intention-to-treat population, included solicited adverse events within 7 days of vaccination (assessed on 3 separate days) and unsolicited adverse events within 28 days of vaccination. This trial is registered with ClinicalTrials.gov, NCT03299426.FindingsBetween Feb 22 and Sept 6, 2018, 664 participants were screened, and 631 participants were enrolled and randomly assigned (320 to the TCV group and 311 to the MCV-A group). 305 participants in the TCV group and 297 participants in the MCV-A group were vaccinated. Among TCV recipients, anti-Vi IgG geometric mean titres increased more than 500 times from 4·2 ELISA units (EU)/mL (95% CI 4·0–4·4) at baseline to 2383·7 EU/mL (2087·2–2722·3) at day 28, then decreased to 48·0 EU/mL (39·9–57·8) at day 730–1035, remaining more than 11 times higher than baseline. Among MCV-A recipients, anti-Vi IgG titres remained unchanged: 4·3 EU/mL (4·0–4·5) at baseline, 4·4 EU/mL (4·0–4·7) on day 28, and 4·6 EU/mL (4·2–5·0) on day 730–1035. TCV and MCV-A recipients had similar solicited local (eight [3%] of 304, 95% CI 1·3–5·1 and three [1%] of 293, 0·4–3·0) and systemic (27 [9%] of 304, 6·2–12·6 and 27 [9%] of 293, 6·4–13·1) reactogenicity. Related unsolicited adverse events occurred similarly in TCV and MCV-A recipients in eight (3%) of 304 (1·3–5·1) and eight (3%) of 293 (1·4–5·3).InterpretationThis study provides evidence of TCV safety, tolerability, and immunogenicity up to 730–1035 days in Malawian children aged 9 months to 12 years.FundingBill & Melinda Gates Foundation.