A New Vaccine for Tuberculosis: The Challenges of Development and Deployment

Tuberculosis (TB) is one of the world’s leading causes of death due to infection and efforts to control TB would be substantially aided by the availability of an improved TB vaccine. There are currently nine new TB vaccines in clinical development, and the first efficacy trials are due to commence in 2009. There are many complex ethical issues which arise at all stages of TB vaccine development, from the need to conduct trials in developing countries to informed consent and the process of ethical review. While it is important that these issues are discussed, it may also be timely to consider the challenges which may arise if a vaccine in clinical development proves to be highly effective. We examine a number of scenarios where decisions on the deployment of a new TB vaccine may impact on the rights and liberty of the individual. Competing Interest Statement  Helen McShane is an inventor on a composition of matter patent and a shareholder in a Joint Venture, Oxford-Emergent Tuberculosis Consortium, formed to develop MVA85A. The views expressed in this article are those of the author(s) and do not necessarily represent those of the Oxford-Emergent Tuberculosis Consortium Ltd     

Vibriocidal Antibody Responses to a Bivalent Killed Whole-Cell Oral Cholera Vaccine in a Phase III Trial in Kolkata,India

Background

During the development of a vaccine, identification of the correlates of protection is of paramount importance for establishing an objective criterion for the protective performance of the vaccine. However, the ascertainment of correlates of immunity conferred by any vaccine is a difficult task.

Methods

While conducting a phase three double-blind, cluster-randomized, placebo-controlled trial of a bivalent killed whole-cell oral cholera vaccine in Kolkata, we evaluated the immunogenicity of the vaccine in a subset of participants. Randomly chosen participants (recipients of vaccine or placebo) were invited to provide blood samples at baseline, 14 days after the second dose and one year after the first dose. At these time points, serum geometric mean titers (GMT) of vibriocidal antibodies and seroconversion rates for vaccine and placebo arms were calculated and compared across the age strata (1 to 5 years, 5 to 15 years and more than 15 years) as well as for all age groups.

Results

Out of 137 subjects included in analysis, 69 were vaccinees and 68 received placebo. There were 5•7 and 5•8 geometric mean fold (GMF) rises in titers to Vibrio cholerae Inaba and Ogawa, respectively at 14 days after the second dose, with 57% and 61% of vaccinees showing a four-fold or greater titer rise, respectively. After one year, the titers to Inaba and Ogawa remained 1•7 and 2•8 fold higher, respectively, compared to baseline. Serum vibriocidal antibody response to V. cholerae O139 was much lower than that to Inaba or Ogawa. No significant differences in the GMF-rises were observed among the age groups.

Conclusions

The reformulated oral cholera vaccine induced a statistically significant anti-O1 Inaba and O1 Ogawa vibriocidal antibody response 14 days after vaccination, which although declined after one year remained significantly higher than baseline. Despite this decline, the vaccine remained protective five years after vaccination.     

Safety and Immunogenicity of a Live Oral Recombinant Cholera Vaccine VA1.4: A Randomized,Placebo Controlled Trial in Healthy Adults in a Cholera Endemic Area in Kolkata,India

Background

A live oral cholera vaccine VA 1.4 developed from a non-toxigenic Vibrio cholerae O1 El Tor strain using ctxB gene insertion was further developed into a clinical product following cGMP and was evaluated in a double-blind randomized placebo controlled parallel group two arm trial with allocation ratio of 1∶1 for safety and immunogenicity in men and women aged 18–60 years from Kolkata, India.

Method

A lyophilized dose of 1.9×10⁹ CFU (n = 44) or a placebo (n = 43) reconstituted with a diluent was administered within 5 minutes of drinking 100 ml of a buffer solution made of sodium bicarbonate and ascorbic acid and a second dose on day 14.

Result

The vaccine did not elicit any diarrhea related adverse events. Other adverse events were rare, mild and similar in two groups. One subject in the vaccine group excreted the vaccine strain on the second day after first dose. The proportion of participants who seroconverted (i.e. had 4-folds or higher rise in reciprocal titre) in the vaccine group were 65.9% (95% CI: 50.1%–79.5%) at both 7 days (i.e. after 1^st dose) and 21 days (i.e. after 2^nd dose). None of the placebo recipients seroconverted. Anti-cholera toxin antibody was detected in very few recipients of the vaccine.

Conclusion

This study demonstrates that VA 1.4 at a single dose of 1.9×10⁹ is safe and immunogenic in adults from a cholera endemic region. No additional benefit after two doses was seen.

Trial Registration

Clinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2012/04/002582     

An Open Label Non-inferiority Trial Assessing Vibriocidal Response of a Killed Bivalent Oral Cholera Vaccine Regimen following a Five Year Interval in Kolkata,India

Background

The bivalent killed oral cholera vaccine (OCV) provides 65% cumulative protection over five years. It remains unknown whether a boosting regimen can maintain protection in previously immunized populations. This study examines the immunogenicity and safety of an OCV regimen given five years following initial dosing.

Methodology/Principal Findings

An open label controlled trial was conducted in 426 healthy Indian participants previously enrolled in a large efficacy trial. To assess whether an OCV regimen given after five years can elicit an antibody response equal to that of a primary series, we compared vibriocidal antibody titers in previously immunized participants receiving a two dose booster regimen to participants receiving a primary two dose immunization series. Among participants receiving a two dose primary series of OCV (n = 186), 69% (95% CI 62%-76%) seroconverted. In the intervention arm (n = 184), 66% (95% CI 59%-73%) seroconverted following a two dose boosting schedule given five years following the initial series. Following a single boosting dose, 71% (95% CI 64%-77%) seroconverted. Children demonstrated 79% (95% CI 69%-86%) and 82% (95% CI 73%-88%) seroconversion after primary and boosting regimens, respectively.

Conclusions/Significance

Administration of an OCV boosting regimen elicits an immune response similar to those receiving a primary series in endemic areas. Though a single boosting dose induces a strong immune response, further investigations are needed to measure if these findings translate to clinical protection.     

霍乱毒素B亚单位在疫苗研究中的应用

CTB不同于CT,没有毒性,在体内和体外CTB具有强的免疫调节活性。越来越多的证据表明CTB在疫苗研究中发挥重要作用。深入理解CTB的免疫调节机制及其在疫苗研究中的应用,有助于设计新疫苗和改良疫苗。因此,将对CTB在疫苗研究中的应用进展进行综述。     

Dynamics Analysis of a Multi-strain Cholera Model with an Imperfect Vaccine

A new two-strain model, for assessing the impact of basic control measures, treatment and dose-structured mass vaccination on cholera transmission dynamics in a population, is designed. The model has a globally-asymptotically stable disease-free equilibrium whenever its associated reproduction number is less than unity. The model has a unique, and locally-asymptotically stable, endemic equilibrium when the threshold quantity exceeds unity and another condition holds. Numerical simulations of the model show that, with the expected 50 % minimum efficacy of the first vaccine dose, vaccinating 55 % of the susceptible population with the first vaccine dose will be sufficient to effectively control the spread of cholera in the community. Such effective control can also be achieved if 50 % of the first vaccine dose recipients take the second dose. It is shown that a control strategy that emphasizes the use of antibiotic treatment is more effective than one that emphasizes the use of basic (non-pharmaceutical) anti-cholera control measures only. Numerical simulations show that, while the universal strategy (involving all three control measures) gives the best outcome in minimizing cholera burden in the community, the combined basic anti-cholera control measures and treatment strategy also has very effective community-wide impact.     

O139型霍乱菌苗人群副反应观察报告

在广西田阳县中学生中,分６组共６９７人进行了Ｏ１３９型霍乱菌苗与Ｏ１群霍乱菌苗的双盲、有对照的人体反应现场观察。结果表明,不加铝佐剂的Ｏ１３９型霍乱菌苗及Ｏ１群霍乱菌苗,不论是低剂量组（两剂全程接种４５亿菌体）抑或常剂量组（全程接种９０亿）接种人群均可产生１０～２５％的体温呈轻度升高的弱反应,并且同种菌苗的两剂量组的反应率无显著差异;第一剂接种的反应率（１９～２５％）较第二剂接种的（１０～１５％）高,Ｐ＜０．０５;接种局部反应轻微,只有个别受试者出现直径小于１５ｍｍ的硬结;加佐剂的Ｏ１群吸附霍乱菌苗的反应较其它组强。结果证实,甲醛灭活的Ｏ１３９型霍乱菌苗和Ｏ１群霍乱菌苗是安全的,接种人体对之具有良好的耐受性     

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

BackgroundIn 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both.ConclusionsReactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign.     

Age-Dependent Association among Helicobacter pylori Infection,Serum Pepsinogen Levels and Immune Response of Children to Live Oral Cholera Vaccine CVD 103-HgR

Background

Through its effects on gastric secretion, we hypothesized that Helicobacter pylori infection may influence oral immunization. Accordingly, we examined the association between H. pylori infection, serum pepsinogen (PG) (measures for H. pylori gastritis) and vibriocidal antibody (a correlate of protection) seroconversion following oral immunization with CVD 103-HgR live cholera vaccine among children of different ages.

Methods

Sera from 422 Chilean children who were vaccinated with a single dose of CVD 103-HgR were tested by ELISA for serum IgG antibodies to H. pylori, PG I and PG II levels and antibodies to Shigella flexneri 2a lipopolysaccharide and hepatitis A virus (as markers of low socioeconomic status and exposure to enteric pathogens).

Results

The likelihood of vibriocidal antibody seroconversion following vaccination with CVD 103-HgR was significantly decreased in H. pylori-seropositive children age 6 months to 4 years with PG II>8 µg/L (adjusted OR 0.14 (95% CI 0.03–0.61; P = 0.009), and also in H. pylori seropositives with lower PG II level (adjusted OR 0.34, 95% CI 0.14–0.83; P = 0.017), compared to H. pylori-seronegatives. H. pylori-seropositive children aged 5–9 years with serum PG I>30 µg/L (indicating more severe gastritis) had higher odds of vibriocidal seroconversion than those with lower PG I levels (adjusted OR 4.41, 95%CI 1.26–15.38; P = 0.02). There was no significant association between exposures to S. flexneri 2a or hepatitis A virus and vibriocidal seroconversion.

Conclusions

As H. pylori gastritis progresses with increasing pediatric age in developing country venues, changes in gastric secretion ensue that we believe explain the observed differences in age-related immune responses to immunization with live oral cholera vaccine. The effect of H. pylori and changes of gastric acid secretion on the immunogenicity of various oral vaccines should be studied in different developing, transitional and industrialized country settings.     

Safety of the Recombinant Cholera Toxin B Subunit, Killed Whole-Cell (rBS-WC) Oral Cholera Vaccine in Pregnancy

Introduction

Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy should cholera occur in these women, as well as the lack of expected adverse events from a killed oral bacterial vaccine.

Methodology/Principal Findings

From January to February 2009, a mass rBS-WC vaccination campaign of persons over two years of age was conducted in an urban and a rural area (population 51,151) in Zanzibar. Pregnant women were advised not to participate in the campaign. More than nine months after the last dose of the vaccine was administered, we visited all women between 15 and 50 years of age living in the study area. The outcome of pregnancies that were inadvertently exposed to at least one oral cholera vaccine dose and those that were not exposed was evaluated. 13,736 (94%) of the target women in the study site were interviewed. 1,151 (79%) of the 1,453 deliveries in 2009 occurred during the period when foetal exposure to the vaccine could have occurred. 955 (83%) out of these 1,151 mothers had not been vaccinated; the remaining 196 (17%) mothers had received at least one dose of the oral cholera vaccine. There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies.

Conclusions/Significance

We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial vaccine, are reassuring but the study had insufficient power to detect infrequent events.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00709410","term_id":"NCT00709410"}}NCT00709410     

冻干口服霍乱rBS—WC菌苗安全及保护效果评价的小鼠模型探讨

本文仿照人口服免疫程序用小鼠为模型对冻干口服霍乱ｒＢＳ－ＷＣ菌苗制品进行了安全及保护率评价。给ＫＭ小鼠口服三种不同剂量的ｒＢＳ－ＷＣ菌苗后,无发病,无体重减轻,无死亡现象,表明该菌苗安全,无毒副作用。免疫组与安慰剂组小鼠用肠结扎攻毒试验评价保护效果,两组小鼠用吴江－２及滨－４３活菌攻击后,免疫组显示良好保护作用（Ｐ＜０．０５）。此法可以用于口服型ｒＢＳ－ＷＣ菌苗的评价,但也存在需要动物数较多,个体间差异较大,手术较麻烦的问题。     

Helicobacter pylori Infection, Intestinal Metaplasia, and Gastric Cancer Risk in Eastern Siberia

Background: The incidence of gastric cancer (GC) is extremely high in Russia and eastern Siberia, where information on the epidemiology of Helicobacter pylori infection is fragmentary. Aims: To assess the prevalence of both H. pylori infection (including CagA status) and intestinal metaplasia (IM) in Russian and eastern Siberian populations carrying a different risk of GC. Materials and Methods: A sample of 2129 consecutive patients was considered, including 689 Europoids and 1440 Mongoloids (493 Evenks, 533 Khakass people, and 414 Tuvans), who all underwent serum sampling and upper gastrointestinal endoscopy. H. pylori status was established (ELISA, urease test, and histology), and IgG anti‐CagA antibodies were assessed (ELISA) in H. pylori‐positive cases. At least 3 biopsy samples per patient were considered, and IM was scored as present versus absent. The prevalence of H. pylori, CagA+ve status, and IM was compared with the incidence of GC according to the regional cancer registries. Results: The prevalence of H. pylori was similar for the Europoids and Mongoloids (93.6 vs 94.3%). The prevalence of CagA+ve infection was as follows: Europoids 61.2%, Evenks 36.4%, Khakass 44.0%, Tuvans 60.0% (p_1vs2 < .001; p_1vs3 < .001; p_2vs4 < .001; p_3vs4 < .001). The prevalence of IM was as follows: Europoids 10.7%, Evenks 5.1%, Khakass 9.8%, and Tuvans 23.4% (p_1vs2 = .001; p_1vs4 < .001; p_2vs4 < .001; p_3vs4 < .001). The incidence of GC (per 100,000 population/year) was as follows: Europoids 33.2; Evenks 18.2; Khakass 20.2; Tuvans 50.7 (p_1vs2 = 0.04; p_1vs3 = .05; p_2vs4 < .001; p_3vs4 < .001). Conclusion: H. pylori infection is consistently high in Russian and eastern Siberian populations; ethnicities with similar prevalence of CagA+ve status had different prevalence of IM and incidence of GC. As expected, IM prevalence correlated with the incidence of GC. Host‐related and/or environmental factors may explain discrepancies between H. pylori status, the prevalence of IM, and the incidence of GC.