Inactivated rotavirus vaccines: a priority for accelerated vaccine development

Live oral rotavirus vaccines have proven to be generally safe and effective to prevent severe dehydrating diarrhea among children in high and some middle income countries. However, concerns linger about rare but severe adverse events, such as intussusception and their efficacy against the full range of rotavirus serotypes. More importantly, live oral vaccines have been less immunogenic and results of trials to assess their efficacy in poor children of both Africa and Asia will not be available for 2-3 years. This review describes the rationale for developing an inactivated rotavirus vaccine (IRV) as an alternative approach should live oral vaccines not work well in these challenging populations. Studies have demonstrated the protective role of serum antibody in animals and children and the robust serum antibody response and protection against rotavirus infection in animal models following parenteral immunization with IRV. Four years after licensing the first new generation of rotavirus vaccine, we still remain several years away from knowing how well they work in the target populations. Research to develop alternative approaches should be fostered as an insurance policy to protect against suboptimal efficacy or unanticipated adverse events that could hinder global immunization and protection of all children.     

Development of priority vaccines for disease-endemic countries: risk and benefit

Decisions regarding vaccine regulation and use made by institutions in industrialized countries can have an unintended impact on vaccines' availability in disease-endemic countries. However, regulatory and programmatic decision making by such countries, taking into consideration local risks and benefits, requires adequate resources, both human and financial. Such differing risk-benefit determinations between industrialized and disease-endemic countries will increase product divergence. We propose a single universal standard for risk assessment, based on maximizing net benefit, and an action plan to improve access to priority vaccines through a more robust determination of risk and benefit.     

Adjuvant effect of DEAE-dextran on cholera vaccines

Investigations into the effectiveness of DEAE-dextran as an adjuvant of whole cell cholera vaccines (Vibrio cholerae Inaba and Ogawa serotypes) were conducted using two methods: (a) the active mouse protection test, (b) the determination of antibody production in the sera of immunized mice by measuring the level of vibriocidal antibodies, and by an enzyme-linked immunosorbent assay (ELISA). In all tests, the DEAE-dextran-adjuvanted vaccine showed an antigenicity substantially superior to that achieved without adjuvants.     

Roadmap for the international collaborative epidemiologic monitoring of safety and effectiveness of new high priority vaccines

With the advent of new vaccines targeted to highly endemic diseases in low- and middle-income countries (LMIC) and with the expansion of vaccine manufacturing globally, there is an urgent need to establish an infrastructure to evaluate the benefit-risk profiles of vaccines in LMIC. Fortunately the usual decade(s)-long time gap between introduction of new vaccines in high and low income countries is being significantly reduced or eliminated due to initiatives such as the Global Alliance for Vaccines and Immunizations (GAVI) and the Decade of Vaccines for the implementation of the Global Vaccine Action Plan. While hoping for more rapid disease control, this time shift may potentially add risk, unless appropriate capacity for reliable and timely evaluation of vaccine benefit-risk profiles in some LMIC's are developed with external assistance from regional or global level. An ideal vaccine safety and effectiveness monitoring system should be flexible and sustainable, able to quickly detect possible vaccine-associated events, distinguish them from programmatic errors, reliably and quickly evaluate the suspected event and its association with vaccination and, if associated, determine the benefit-risk of vaccines to inform appropriate action. Based upon the demonstrated feasibility of active surveillance in LMIC as shown by the Burkina Faso assessment of meningococcal A conjugate vaccine or that of rotavirus vaccine in Mexico and Brazil, and upon the proof of concept international GBS study, we suggest a sustainable, flexible, affordable and timely international collaborative vaccine safety monitoring approach for vaccines being newly introduced. While this paper discusses only the vaccine component, the same system could also be eventually used for monitoring drug effectiveness (including the use of substandard drugs) and drug safety.     

UK vaccines network: Mapping priority pathogens of epidemic potential and vaccine pipeline developments

During the 2013–2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods.     

The effect of misclassification on evaluating the effectiveness of influenza vaccines

Misclassification is a measurement error and can be considered a type of information bias. Misclassification can occur at both exposure and outcome levels. Nondifferential misclassification causes only a dilution effect leading to underestimation, whereas differential misclassification can have more complicated and serious consequences. To avoid nondifferential diagnosis misclassification, it is necessary to use highly specific diagnostic examinations or criteria such as virus detection to exclude 'false positive' cases, and to limit the observation period to an intensive epidemic period if using less specific diagnostic criteria such as symptoms of influenza-like illness (ILI) or absence from school or workplace. To avoid differential diagnosis misclassification, vaccinated and unvaccinated groups must be equally scrutinized, and such scrutiny is more important than the specificity of diagnosis. So, passive findings from patients with influenza at clinics can cause complicated differential misclassification despite use of highly specific diagnostic procedures because vaccinated and unvaccinated patients may participate differently. Also important is standardization of diagnostic procedure that vaccination anamnesis does not influence diagnosis of influenza, or examination of the influence. Exposure misclassification would mainly underestimate vaccine effectiveness in most situations. Consequently, misclassification of diagnosis, especially differential misclassification, affects evaluation of influenza vaccine effectiveness.     

Lysed BCG vaccines. 2. The effect of lysis on the immunogenicity and allergenicity of BCG vaccines

The authors have attempted to prepare lysed BCG vaccines retaining the protective antigens of the BCG cell wall and yet eliciting in experimental animals limited sensitivity to the tuberculin substances, the advantage sought being to retain the usefulness of the tuberculin following vaccination as an indicator of superinfection.