Vaccine
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Randomized Controlled Trial Comparative Study
Improved CD4⁺ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial.
The Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 μg of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 μg dose), M72 in saline (40 μg dose) and AS01 alone. ⋯ This first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.
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Respiratory syncytial virus infection remains a serious health problem, not only in infants but also in immunocompromised adults and the elderly. An effective and safe vaccine is not available due to several obstacles: non-replicating RSV vaccines may prime for excess Th2-type responses and enhanced respiratory disease (ERD) upon natural RSV infection of vaccine recipients. We previously found that inclusion of the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA) in reconstituted RSV membranes (virosomes) potentiates vaccine-induced immunity and skews immune responses toward a Th1-phenotype, without priming for ERD. ⋯ In cotton rats, similar effects of incorporation of MPLA in virosomes were observed with respect to induction of systemic antibodies and inhibition of lung viral shedding upon challenge, but mucosal sS-IgA responses were only moderately enhanced. Importantly, IN immunization with RSV-MPLA virosomes, like live virus infection, did not lead to any signs of ERD upon live virus challenge of vaccinated animals, whereas IM immunization with FI-RSV did induce severe lung immunopathology under otherwise comparable conditions. Taken together, these data show that mucosally administered RSV-MPLA virosomes hold promise for a safe and effective vaccine against RSV.
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Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. These organisms cause a wide spectrum of disease, ranging from uncomplicated sore throat to invasive, life-threatening infections, as well as immune complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and acute post-streptococcal glomerulonephritis (APSGN). Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. ⋯ Some of the obstacles to GAS vaccine development are related to the complexity of the global epidemiology of GAS infections, the limitation in the criteria for selection of antigens to include in combination vaccines as well as the issues around autoimmunity and vaccine safety, among others. Overcoming these obstacles will require collaborative efforts to develop innovative strategies that address key steps in the pre-clinical and clinical development process, as well as clearly defining the global burden of GAS diseases and the molecular epidemiology of infections. Specific recommendations are presented for an accelerated plan leading to the introduction of a broadly protective vaccine designed for deployment in low-, middle-, and high-income countries.
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The Decade of Vaccines Global Vaccine Action Plan has outlined a set of ambitious goals to broaden the impact and reach of immunization across the globe. A projections exercise has been undertaken to assess the costs, financing availability, and additional resource requirements to achieve these goals through the delivery of vaccines against 19 diseases across 94 low- and middle-income countries for the period 2011-2020. The exercise draws upon data from existing published and unpublished global forecasts, country immunization plans, and costing studies. ⋯ About 57% of the total resources required to close the funding gap are needed just to maintain existing programs and scale up other currently available vaccines (i.e., before adding in the additional costs of vaccines still in development). Efforts to mobilize additional resources, manage program costs, and establish mutual accountability between countries and development partners will all be necessary to ensure the goals of the Decade of Vaccines are achieved. Establishing or building on existing mechanisms to more comprehensively track resources and commitments for immunization will help facilitate these efforts.
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From August to December 2011, a multidisciplinary group with expertise in mathematical modeling was constituted by the GAVI Alliance and the Bill & Melinda Gates Foundation to estimate the impact of vaccination in 73 countries supported by the GAVI Alliance. ⋯ Vaccination of persons during 2011-2020 in 73 GAVI-eligible countries is expected to have substantial public health impact, particularly in Africa and Southeast Asia, two regions with high mortality. The actual impact of vaccination in these countries may be higher than our estimates because several widely used antigens were not included in the analysis. The quality of our estimates is limited by lack of data on underlying disease burden and vaccine effectiveness against fatal disease outcomes in developing countries. We plan to update the estimates annually to reflect updated demand forecasts, to refine model assumptions based on results of new information, and to extend the analysis to include morbidity and economic benefits.