The TB vaccine development pathway - An innovative approach to accelerating global TB vaccine development.

Two proof of concept clinical trials with TB vaccines demonstrate that new approaches can prevent sustained TB infection in adolescents (BCG revaccination) and TB disease in adults (M72/ASO1) (Nemes et al., 2018; Tait et al., 2019) [1,2].

Preferred product characteristics for therapeutic vaccines to improve tuberculosis treatment outcomes: Key considerations from World Health Organization consultations.

Treating tuberculosis (TB) requires a multidrug course of treatment lasting 6 months, or longer for drug-resistant TB, which is difficult to complete and often not well tolerated. Treatment failure and recurrence after end-of-treatment can have devastating consequences, including progressive debilitation, death, the transmission of Mycobacterium tuberculosis - the infectious agent responsible for causing TB - to others, and may be associated with the development of drug-resistant TB. The burden on health systems is important, with severe economic consequences.

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial.

Background: Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.

Methods: We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa.

Human challenge trials in vaccine development: Strasbourg, September 29 - October 1, 2014.

An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product.

Predictive markers of safety and immunogenicity of adjuvanted vaccines.

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field.

Pneumococcal conjugate vaccines and otitis media: an appraisal of the clinical trials.

Streptococcus pneumoniae is the predominant otitis media pathogen and its prevention through effective vaccination could diminish childhood illness and antibiotic use. This paper reviews 5 pneumococcal conjugate vaccine (PCV) trials that used otitis media as an endpoint: Northern California Kaiser Permanente (NCKP; vaccine, 7-valent PCV [PCV7]-CRM); Finnish Otitis Media (FinOM; vaccines, PCV7-CRM or PCV7-OMPC); Native American Trial (vaccine, PCV7-CRM); Pneumococcal Otitis Efficacy Trial (POET; vaccine, 11-valent PCV [PCV11]-PD). For the microbiological endpoint, vaccine efficacy against vaccine-serotype pneumococcal otitis media was about 60% across trials.

The relationship between pneumococcal serotypes and antibiotic resistance.

Streptococcus pneumoniae (SP) causes significant burden of disease, including invasive pneumococcal disease and noninvasive diseases such as pneumonia and acute otitis media. SP has at least 93 different capsular serotypes, with the various serotypes having different propensities for producing disease or developing antibiotic resistance. An increase in the prevalence of antibiotic-resistant SP serotypes has been observed globally.

Risk factors for serotype 19A carriage after introduction of 7-valent pneumococcal vaccination.

Background: After the implementation of 7-valent pneumococcal conjugate vaccine (PCV7), in several countries, serotype 19A is now the serotype most frequently involved in pneumococcal diseases and carriage. To determine factors potentially related to 19A nasopharyngeal (NP) carriage we analyzed data from an ongoing prospective French national surveillance study of pneumococcal NP carriage in young children.

Methods: NP swabs were obtained from children aged 6 to 24 months, either during routine check-ups with normal findings, or when they presented with acute otitis media (AOM).

Pneumococcal polysaccharide-protein CRM197 conjugate vaccines, 7- or 9-valent, in the 2 + 1 schedule.

The 7-valent pneumococcal polysaccharide-protein (CRM(197)) conjugate vaccine (PCV-7) was licensed based on clinical efficacy trials using the four-dose schedule of three infant doses and a booster dose in the second year of life (3 + 1). An assessment of PCV-7 immunogenicity in studies evaluating two infant doses with a booster (2 + 1) showed similar immunogenicity for the 2 + 1 and 3 + 1 schedules, with the exception of lower post-dose two responses for serotypes 6B and 23F, compared with a three-dose primary series. The 2 + 1 PCV-7 schedule has been shown to be effective in controlling pneumococcal disease in several countries, as used in national immunization programs that are marked in particular by good uptake, compliance with the booster dose and application of a catch-up program.

Nasopharyngeal carriage of Streptococcus pneumoniae shortly before vaccination with a pneumococcal conjugate vaccine causes serotype-specific hyporesponsiveness in early infancy.

Background: The antibody response to pneumococcal conjugate vaccines (PCVs) in infants is variable. Factors responsible for this variability have not been fully elucidated. The objective of this study was to investigate whether pneumococcal carriage around the time of the first dose of 7-valent PCV (PCV7) affects serotype-specific immunologic response.

A new endpoint definition improved clinical relevance and statistical power in a vaccine trial.

Objective: Endpoints used for the evaluation of immunogenicity in vaccine trials are often the proportion of individuals with immune response or geometric means of antibody concentrations for each serotype. When a vaccine includes several types of the same species, we illustrate how an endpoint combining all responses may improve clinical relevance and statistical power.

Study Design And Settings: The motivating example was the ANRS 114 Pneumovac trial where the effect of two vaccine strategies against Streptococcus pneumoniae was assessed in adults infected by the Human Immunodeficiency Virus.

Pneumococcal conjugate vaccine does not influence Staphylococcus aureus carriage in young children with acute otitis media.

We investigated nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus among infants and young children with acute otitis media in a country where use of 7-valent pneumococcal conjugate vaccine (PCV7) has been progressively implemented. Among 1783 children enrolled, 60.8% carried S.

Influenza burden in febrile infants and young children in a pediatric emergency department.

Background: In France, epidemiologic data in children in ambulatory settings are scarce. We aimed to measure the burden of influenza in young children.

Methods: Febrile children younger than 36 months were consecutively recruited in a pediatric emergency department during the 2002 epidemic peak.

Impact of pneumococcal conjugate vaccine and of reduction of antibiotic use on nasopharyngeal carriage of nonsusceptible pneumococci in children with acute otitis media.

Background: Penicillin resistance among pneumococci has increased in the past 15 years. The implementation of widespread vaccination with the heptavalent pneumococcal conjugate vaccine (PCV7) and the reduction of inappropriate antibiotic use could help reduce antibiotic resistance.

Methods: Between September 2001 and June 2004, 89 pediatricians distributed throughout France took part in this prospective study.

Indirect effects associated with widespread vaccination of infants with heptavalent pneumococcal conjugate vaccine (PCV7; Prevnar).

Prevnar (heptavalent pneumococcal conjugate vaccine; PCV7) provides protection against invasive pneumococcal disease (IPD) caused by vaccine serotypes. Indirect protection of non-immunised individuals may be the consequence of decreased transmission of vaccine serotypes, generally carried in the nasopharynx of infants and young children. This review summarises published reports of IPD incidence (1998-2005) among non-immunised individuals in countries with universal PCV7 immunisation.

Brief review of the clinical effectiveness of PREVENAR against otitis media.

Pre-licensure trials in Finnish and US infants demonstrated that PREVENAR was associated, respectively, with a 6% (95% CI, -4% to 16%) and an 8.9% (95% CI, 5.8-11.

Pneumococcal conjugate vaccines: emerging clinical information and its implications.

Since 2000, when the first pneumococcal conjugate vaccine was introduced into routine use in the USA, it has had a substantial impact on invasive pneumococcal disease both in the immunized and nonimmunized population. It has also been shown to reduce pneumonia and otitis in young children and has reduced antibiotic nonsusceptible pneumococcal infections. In the USA, three primary doses and a booster dose are recommended (a so-called '3 + 1 schedule').

Early appearance of bactericidal antibodies after polysaccharide challenge of toddlers primed with a group C meningococcal conjugate vaccine: what is its role in the maintenance of protection?

The contribution of memory responses after meningococcal vaccination to protection may depend on the rapidity of the response. Toddlers were challenged with a licensed polysaccharide (PS) vaccine 1 year after vaccination with a single dose of meningococcal group C-CRM(197) conjugate (MCC) vaccine at the age of 12 to 15 months. Bactericidal antibodies and immunoglobulin G (IgG) antibodies detected by an enzyme-linked immunosorbent assay (ELISA) were measured before challenge and 4, 7, 14, or 21 Days later ("Days" refer to treatment groups, "days" to sampling days).

[Conjugated vaccines].

Encapsulated bacterial pathogens (e.g. Haemophilus influenzae type b [Hib], Neisseria meningitidis, or Streptococcus pneumoniae) target infants and young children who have lost any protective anti-capsular antibodies supplied maternally and whose immune systems are ineffective against T-independent antigens such as the polysaccharides of the capsule.

Time to recommend pneumococcal vaccination for all children in Europe: experience in France.

Unlabelled: The French decision-making processes for recommendation and introduction of infant vaccination with Prevenar reflect a public health-based dialogue between the Direction Générale de la Santé and Wyeth (Paris-La Défense, France) nurtured by open and ongoing exchanges. Three surveillance programmes are being discussed: (1) to ascertain the future impact of large-scale Prevenar vaccination on invasive pneumococcal disease incidence, (2) to follow the evolution and carriage of pneumococcus and (3) to look at the possibilities to establish an epidemiological surveillance and active "vaccinovigilance" in France (to estimate the number of adverse events that might be expected among the population targeted by the vaccination recommendation).

Conclusion: in this way, the Direction Générale de la Santé and Wyeth are working towards the implementation of a broad-scale vaccine introduction.