Aderonke Odutola

Immunogenicity of the Tuberculosis Vaccine MVA85A Is Reduced by Coadministration with EPI Vaccines in a Randomized Controlled Trial in Gambian Infants

Coadministration with standard vaccines may reduce immunogenicity of tuberculosis vaccine. Timing Is Everything Anyone who bought a house right before the housing bubble burst knows that it’s not only what you do but when you do it that matters. Likewise, when introducing a new vaccine, timing is crucial—it may be easier to ensure compliance if the immunization is offered when the patient is already visiting the doctor. However, some vaccines may not be as effective if given at the same time as other shots. Ota et al. explored this phenomenon for a new tuberculosis (TB) vaccine in a clinical trial of Gambian infants. The Expanded Program on Immunization (EPI) provides a country-specific schedule of standard vaccinations to increase vaccine coverage in underserved populations. The current vaccine for TB, Bacille Calmette-Guérin (BCG), is used in the EPI; however, BCG is only partially effective against TB, especially in adults. Ota et al. tested MVA85A, a novel vaccine designed to enhance BCG, in infants in Gambia. They found that MVA85A was safe and well tolerated and successfully induced a cellular immune response in recipients. Coadministration of MVA85A and the EPI vaccines did not affect the antibody responses to the latter but did reduce the immunogenicity of MVA85A. Thus, the EPI schedule may have to be modified for successful vaccination before the introduction of MVA85A and potentially other new T cell–inducing vaccines as well. In vaccination, as in life, timing is everything. New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guérin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell–inducing vaccines.

Comparison of the Prevalence of Common Bacterial Pathogens in the Oropharynx and Nasopharynx of Gambian Infants

Background CRM- based pneumococcal conjugate vaccines generally have little impact on the overall prevalence of pneumococcal carriage because of serotype replacement. In contrast, protein vaccines could substantially reduce the overall prevalence of pneumococcal carriage with potential microbiological and clinical consequences. Therefore, trials of pneumococcal protein vaccines need to evaluate their impact on carriage of other potentially pathogenic bacteria in addition to the pneumococcus. Methods As a prelude to a trial of an investigational pneumococcal vaccine containing pneumococcal polysaccharide conjugates and pneumococcal proteins, the prevalence of carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella species and Staphylococcus aureus in the nasopharynx of 1030 Gambian infants (median age 35 weeks) was determined. An oropharyngeal swab was obtained at the same time from the first 371 infants enrolled. Standard microbiological techniques were used to evaluate the bacterial flora of the pharynx and to compare that found in the oropharynx and in the nasopharynx. Results The overall pneumococcal carriage rate was high. Isolation rates of S. pneumoniae and Moraxella species were significantly higher using nasopharyngeal rather than oropharyngeal swabs (76.1% [95% CI 73.4%,78.7%] vs. 21.3% [95% CI 17.2%,25.8%] and 48.9% [95% CI 45.8%, 52.0%] vs. 20.5% % [95% CI 16.5%,25.0%] respectively). In contrast, S. aureus and H. influenzae were isolated more frequently from oropharyngeal than from nasopharyngeal swabs (65.0% [95% CI 59.9%, 69.8%] vs. 33.6% [95% CI 30.7%, 36.5%] and 31.8% [95% CI 16.5%, 25.0%] vs. 22.4% [95% CI 19.9%, 25.1%] respectively). No group A β haemolytic streptococci were isolated. Conclusion Collection of an oropharyngeal swab in addition to a nasopharyngeal swab will provide little additional information on the impact of a novel pneumococcal vaccine on pneumococcal carriage but it might provide additional, valuable information on the impact of the vaccine on the overall microbiota of the pharynx.

Coverage and timing of children's vaccination: an evaluation of the expanded programme on immunisation in The Gambia.

Objective To evaluate the coverage and timeliness of the Expanded Programme on Immunisation (EPI) in The Gambia. Methods Vaccination data were obtained between January 2005 and December 2012 from the Farafenni Health and Demographic Surveillance System (FHDSS), the Basse Health and Demographic Surveillance System (BHDSS), the Kiang West Demographic surveillance system (KWDSS), a cluster survey in the more urban Western Health Region (WR) and a cross sectional study in four clinics in the semi-urban Greater Banjul area of WR. Kaplan-Meier survival function was used to estimate the proportion vaccinated by age and to assess timeliness to vaccination. Findings BCG vaccine uptake was over 95% in all regions. Coverage of DPT1 ranged from 93.2% in BHDSS to 99.8% in the WR. Coverage decreased with increasing number of DPT doses; DPT3 coverage ranged from 81.7% in BHDSS to 99.0% in WR. Measles vaccination coverage ranged from 83.3% in BHDSS to 97.0% in WR. DPT4 booster coverage was low and ranged from 43.9% in the WR to 82.8% in KWDSS. Across all regions, delaying on previous vaccinations increased the likelihood of being delayed for the subsequent vaccination. Conclusions The Gambia health system achieves high vaccine coverage in the first year of life. However, there continues to be a delay to vaccination which may impact on the introduction of new vaccines. Examples of effectively functioning EPI programmes such as The Gambia one may well be important models for other low income countries struggling to achieve high routine vaccination coverage.

A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants.

This study aimed to evaluate the durability of the immunogenicity of MVA85A beyond infancy. Participants in an immunogenicity study of MVA85A administered at age of 4 months had additional evaluation 14 months after initial vaccination for IFN-γ ELISPOT responses to Ag85A peptide and ESAT6/CFP-10 and tuberculin skin test (TST). 112 children participated in this study. The anthropometry, biochemical and haematological safety profile were similar between the MVA85A recipients and controls. MVA85A recipients still had significantly higher immune responses to Ag85A compared to the controls. The majority of these children had negative responses to the TST as well as the ESAT6/CFP-10 antigens. In summary, MVA85A-vaccinated children had a persistently higher Ag85A immune response 14 months following vaccination than controls. All the children had negligible evidence of latent infection with M. tuberculosis (Mtb), suggesting that deploying a prophylactic vaccine against Mtb infection at this age could still be effective in this setting.

Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2–4 years: A phase II randomized study

Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2–4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD-CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post-vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD-CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype ≥96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype-specific polysaccharide antibody concentrations ≥0.20µg/mL except serotypes 6B (80.8%) and 23F (65.4%), and ≥94.1% had OPA titres of ≥8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2–4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic.

Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: A phase 2, randomized, controlled, observer-blind study

BACKGROUND Conserved pneumococcal proteins are potential candidates for inclusion in vaccines against pneumococcal diseases. In the first part of a two-part study, an investigational vaccine (PHiD-CV/dPly/PhtD-30) containing 10 pneumococcal serotype-specific polysaccharide conjugates (10VT) combined with pneumolysin toxoid and pneumococcal histidine triad protein D (30μg each) was well tolerated by Gambian children. Part two, presented here, assessed the efficacy of two PHiD-CV/dPly/PhtD formulations against pneumococcal nasopharyngeal carriage (NPC) prevalence in infants. METHODS In this phase 2, randomized, controlled, observer-blind trial, healthy infants aged 8-10weeks, recruited from a peri-urban health center, were randomized (1:1:1:1:1:1) into six groups. Four groups received PHiD-CV/dPly/PhtD (10 or 30μg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine at ages 2-3-4months (3+0 infant schedule) and two groups PHiD-CV/dPly/PhtD-30 or PHiD-CV at 2-4-9months (2+1 infant schedule). The primary objective was impact on non-10VT NPC at ages 5-9-12months. Secondary objectives included confirmatory analysis of protein dose superiority and safety/reactogenicity. Impact on pneumococcal NPC acquisition, bacterial load, and ply and phtD gene sequencing were explored. RESULTS 1200 infants were enrolled between June 2011 and May 2012. Prevalences of pneumococcal (60-67%) and non-10VT (55-61%) NPC were high at baseline. Across all post-vaccination time points, efficacy of PHiD-CV/dPly/PhtD-10 and PHiD-CV/dPly/PhtD-30 against non-10VT NPC (3+0 schedule) was 1.1% (95% CI -21.5, 19.5) and 2.1% (-20.3, 20.3), respectively; efficacy of PHiD-CV/dPly/PhtD-30 (2+1 schedule) was 0.5% (-22.1, 18.9) versus PHiD-CV. No differences were observed in pneumococcal NPC acquisition, clearance, or bacterial load. Both protein-based vaccines elicited immune responses to pneumococcal proteins. CONCLUSIONS In this high carriage prevalence setting, inclusion of pneumococcal proteins in the PHiD-CV/dPly/PhtD investigational vaccine had no impact on pneumococcal NPC in infants, regardless of protein dose or schedule. Future evaluations will assess its impact against pneumococcal disease endpoints. FUNDING PATH, GlaxoSmithKline Biologicals SA. ClinicalTrials.gov identifier NCT01262872.

Contextualizing the Informed Consent Process in Vaccine Trials in Developing Countries

Introduction: Most sponsors of clinical trials in Africa propose the use of complicated informed consenting procedures as in developed countries, including the translation of informed consent forms into local languages. Although well intentioned, this practice may be irrelevant and of no added value in settings where local languages are only spoken but not written. Recognizing this challenge, the ethics committee in The Gambia recommend a consent procedure that takes into account these local realities. The objective of this paper was to assess the effectiveness of this new procedure in conveying key trial information among participants in a vaccine trial in The Gambia. Methods: Consent was obtained from 1200 parents using the new procedure. Comprehension was then assessed using a tool that contained questions on key aspects of the trial. Results: Although the majority of respondents had no formal education, almost all of them had a sound understanding of the trial. Variables such as age, gender, education, ethnicity and occupation had minimal effect on comprehension. Discussion and Conclusion: Our data suggest that the new consent procedure is effective in conveying key research information to research participants. The procedure is promising in that it has eliminated the need for repeatedly translating and back-translating informed consents. It also guarantees that the study team expresses research concepts in the same way.

Increased Disease due to Haemophilus influenzae Type b Population-based Surveillance in Eastern Gambia, 2008-2013

Background: In 1997, The Gambia became the first African country to introduce conjugate Haemophilus influenzae type b (Hib) vaccine with good disease control through to 2010. Methods: Culture-based surveillance for invasive bacterial disease in eastern Gambia, specifically the Basse Health and Demographic Surveillance System (BHDSS) area, was conducted from 12 May 2008 and in Fuladu West district from 12 September 2011 until 31 December 2013. In 2011, Hib serology was measured in 5–34-year-olds. Results: In all, 16,735 of 17,932 (93%) eligible patients were investigated. We detected 57 cases of invasive H. influenzae disease; 24 (42%) were type b. No cases of Hib disease were detected in the BHDSS area in 2008–2009; 1 was detected in 2010, 2 in 2011, 4 in 2012 and 7 in 2013. In 2013, the incidence of Hib disease in those aged 2–11 and 2–59 months in the BHDSS area was 88 [95% confidence interval (CI): 29–207] and 22 (95% CI: 9–45) cases per 105 person-years, respectively. In 2013, disease incidence in Fuladu West among those aged 0–59 months was 26 (95% CI: 7–67) cases per 105 person-years. Nine of 24 Hib cases were vaccine failures (2 HIV positive) and 9 were too young to have been vaccinated. The proportion of children aged 5–6 years (n = 223) with anti-Hib IgG ≥1.0 &mgr;g/mL was 67%; the antibody nadir was in 9–14-year-olds (n = 58) with 55% above threshold. Conclusions: Hib disease in eastern Gambia has increased in recent years. Surveillance in developing countries should remain alert to detect such changes.

Haematological and biochemical reference values of Gambian infants

To establish haematological and biological reference values for Gambian infants.

Pneumococcal antibody concentrations and carriage of pneumococci more than 3 years after infant immunization with a pneumococcal conjugate vaccine.

Background A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3–4 years after primary vaccination. Methodology/Principal Findings We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38–52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6–8 weeks and 16–18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6–8 weeks after PCV-7, but only the 6B difference was sustained at 16–18 months. There was no significant difference in nasopharyngeal carriage between the two groups. Conclusions/Significance Pneumococcal antibody concentrations in Gambian children were high 34–48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months.