Procedia in vaccinology最新文献

Veterinary vaccines have had, and continue to have, a major role in protecting animal health and public health, reducing animal suffering, enabling efficient production of food animals to feed the burgeoning human population, and greatly reducing the need for antibiotics to treat food and companion animals. Prominent examples include rabies vaccines and rinderpest vaccines. Rabies vaccines for domestic animals and wildlife have nearly eliminated human rabies in developed countries. Thanks to the Global Rinderpest Eradication Program which involves vaccination, trade restrictions, and surveillance, rinderpest may soon become only the second disease (after smallpox) to be globally eradicated. Successful examples of new technology animal vaccines that are licensed for use, include gene-deleted marker vaccines, virus-like-particle vaccines, recombinant modified live virus vaccines, chimeric vaccines, and DNA vaccines. Animal vaccines also use a wide variety of novel adjuvants that are not yet approved for use in human vaccines. Animal vaccines can be developed and licensed much more quickly than human vaccines. The West Nile virus was discovered in the United States in August 1999. By August 2001, an Equine vaccine for West Nile virus was conditionally licensed. For animal vaccines to effectively protect animal and public health they must be widely used, which means they must be affordable. The regulatory process must meet the need for assuring safety and efficacy without increasing the cost of licensing and production to the point where they are not affordable to the end user.

For live, attenuated vaccines derived from neurotropic wild-type viruses, regulatory authorities require neurovirulence safety testing, typically using monkeys, to assure the absence of residual neurotoxicity. Ethical concerns surrounding the use of nonhuman primates in product testing, coupled with questions over its predictive value, has resulted in a concerted effort to replace monkey-based neurovirulence safety testing with more informative, validated alternative methods that include the use of lower animal species (e.g., mice and rats) and/or in vitro assays such as mutation analysis by PCR and restriction enzyme cleavage (MAPREC). MAPREC is a WHO-approved screening tool to assess reversion to neurovirulence of oral poliovirus vaccine (OPV). Monitoring the genetic consistency of OPV lots by identification and quantification of the mutational profile using the recently developed technology of massively parallel sequencing (MPS) also holds promise not only as a replacement for nonhuman primate testing of OPV lots but for other vaccines for which animal-based tests are currently performed as a measure of manufacturing consistency and freedom of adventitious virus contamination. In many cases, the greatest hurdle to availability of such alternative methods has been the process rather than the science. This report summarizes the current status of alternative methods of neurovirulence safety testing, both those validated and those currently in development.

NICEATM and ICCVAM convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing methods, and to identify opportunities to advance new and improved methods that can further reduce, refine, and replace animal use. This report addresses methods and strategies identified by workshop participants for replacement of animals used for potency testing of human vaccines. Vaccines considered to have the highest priority for future efforts were (1) vaccines for which antigen quantification methods are already developed but not validated, (2) vaccines/components that require the largest number of animals, (3) vaccines that require an in vivo challenge test, and (4) vaccines with in vivo tests that are highly variable and cause a significant number of invalid tests. Vaccine potency tests identified as the highest priorities for replacement were those for diphtheria and tetanus, pertussis (whole cell and acellular), rabies, anthrax, polio vaccine (inactivated) and complex combination vaccines based on DT or DTwP/aP. Research into understanding the precise mechanism of protection afforded by vaccines and the identification of clinically relevant immunological markers are needed to facilitate the successful implementation of in vitro testing alternatives. This report also identifies several priority human vaccines and associated research objectives that are necessary to successfully implement in vitro vaccine potency testing alternatives.

Companion animals are sensitive species able to strongly react to vaccine. Compared to farmanimals, owner’ s sensibility to vaccine safety is exacerbated due to emotional links between animal and owner. Adjuvant selection during vaccine development is a key parameter driving vaccine safety and efficacy profile. Our studies demonstrated the ability to use Montanide™ PetGel A (polymeric adjuvant manufactured under GMP rules) in cat, dog and horse vaccines. Adjuvants performances were highlighted by local and general safety parameters but also through vaccine efficacy to trigger a protective immune response against the pathogen. Three trials were performed to validate Montanide™ PetGel A compatibility with cats, dogs and horses vaccine models. Experimental vaccines were formulated using different antigens according to the animal: inactivated Rhodococcus equi (horse), purified ovalbumin (cat) Leptospira Icterohaemorrhagiae (dogs). In all trials, safety was followed through behavior and temperature measurement. Furthermore, in dog and cat models, histology studies were performed to assess the local reaction in the injection site. A kineticofblood sampling was performed in all trials. Antigen specific ELISAwas used to assess the immune response induced. In cat and dog trials, aluminiumbased formulation were used as benchmark for Montanide™ formulationwhile in horse we compare Montanide™ PetGel Abased vaccine to an already published internal reference. Safety performances ofMontanide™ Pet GelA were superior to aluminium based vaccines in dogs and cats. Transient oedemas were observed in horse vaccine model after each vaccine injection, nevertheless, no impact on the animal behaviorwas observed. The antibodies production induced by Montanide™ PetGel Abased vaccineswas higher than aluminiumbased vaccines or internal reference. Montanide™ PetGel A can be used associated with a wide range ofantigenic media and recommended to be used as adjuvant for sensitive animal’ s vaccines.

Few medical interventions compete with vaccines for their cumulative impact on health and well-being of entire populations. Routine immunization of children in the United States now targets 16 vaccine-preventable diseases; and vaccines are now routinely given across the lifespan. Immunization efforts achieved the global eradication of smallpox, as well as the elimination of polio, measles, and rubella from the Americas. The childhood vaccine series including DTP, polio, MMR, Hib, hepatitis B, and varicella vaccines is estimated to prevent 14 million infections, avoid 33,000 premature deaths, and save $9.9 billion in direct medical costs as well as $33 billion in indirect costs for each U.S. birth cohort fully vaccinated. Newer vaccines such as pneumococcal conjugate, rotavirus, and hepatitis A vaccines have also reduced illness and hospitalizations among the target populations but also have amplified benefits beyond their direct effects through reduced transmission from those immunized to other groups. Although for most of the 20^th century there was a substantial delay between a vaccine's introduction in developed countries and its broad use in poor countries, newer global public–private partnerships and advocacy are leading to accelerated uptake of new and underutilized vaccines. Since the Measles Initiative was established in 2001, more than 700 million children worldwide have received a measles vaccination and an estimated 4.3 million childhood measles deaths have been averted. The full impact of increasing routine immunization further and implementing new vaccines against pneumonia and diarrhea agents in the poorest countries could prevent more than 2 million additional childhood deaths each year.

The Office of Vaccines Research and Review (OVRR) at the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA) regulates preventative and therapeutic vaccines for infectious disease indications for use in humans. The framework for regulation of biological products includes Statutes (e.g. The U.S. Food, Drug and Cosmetic Act and the Public Health Service Act), regulations as defined in the Code of Federal Regulations (CFR) and guidance documents. Approval of a biologics license for a product, including vaccines, is based on a demonstration of safety, purity, and potency and assurance that the facility for manufacture, processing, and packaging meets standards to ensure that product released for distribution is safe, pure and potent. The regulatory definitions of safety, purity and potency are detailed in Title 21 of the Code of Federal regulations (CFR) Part 600. All manufacturing information including tests for safety, purity, and potency for a particular product must be documented in the Biologics License Application (BLA). Potency testing may be performed on the final bulk sample or final container sample and may consist of either in vivo or in vitro tests or both. To change a potency or safety test post-licensure requires a Supplement to the License and data to support a modified or alternative test. CBER encourages the development and use of appropriate alternative methods for vaccine safety and potency testing.

Health Canada (HC) is Canada's national regulatory body that oversees the review, authorization, and lot (batch) release of human vaccines. All biologic drugs, including vaccines, are subject to the Biologics and Genetic Therapies Directorate's Lot Release Program (LRP) before approval and sale. The LRP classifies biologics into one of four risk managed Evaluation Groups based on pre- and post-market evaluation. The extent of lot release testing conducted at HC varies for each group. All vaccines submitted for a Clinical Trial Application or as New Drug Submissions are placed in Group 1a or 1b, respectively. Generally, only Group 1b (manufacturing consistency lots) undergoes targeted testing in addition to a review of manufacturer's test protocols. Targeted testing focuses primarily on potency and can include animal studies, although in vitro assays are favoured when available. In vitro safety assays may also be conducted. Once approved, vaccines are first classified as Group 2 products for which a protocol review and targeted testing are continued. Although HC reserves the right to test all vaccine batches, the percentage of batches tested and types of assays used depends on risk evaluation. Vaccines that are well characterized and have a strong history of consistent manufacture can be placed in Group 3, in which lot release is based on a protocol review with only periodic testing. Vaccines are not placed in Group 4, which is a rapid approval without protocol review for specific biologics. Since its inception in 1995, this testing strategy has led to a significant reduction in animal use at HC.

All animal testing conducted at HC for the LRP is reviewed annually by an Institutional Ethics Review Board and subject to the guidelines established by the Canadian Council on Animal Care, which includes the application of 3R principles. HC remains open to the incorporation of alternative testing strategies for vaccine lot release by (1) reviewing and adopting new assays as they become available and are validated, and (2) contributing to the development of new assays for potency and safety through an active vaccine research program.

The World Health Organization (WHO) has played a key role for over 50 years in establishing the international biological reference preparations necessary to standardize vaccines and other biological substances as well as developing WHO guidelines and recommendations (written standards) on the production, control, nonclinical and clinical evaluation of biological products. These norms and standards, based on scientific consensus achieved through international consultations, assist WHO Member States in ensuring the quality, efficacy and safety of biological medicines and related in vitro biological diagnostic tests worldwide. The Organization accomplishes this work through the WHO Collaborating Centres and the WHO Expert Committee on Biological Standardization. This also involves collaboration with the international scientific and professional communities, regional and national regulatory authorities, manufacturers and expert laboratories worldwide. Through these activities, WHO has supported the concept of replacement, reduction and refinement in use of animals for developing, producing, testing and characterizing vaccines for human use. WHO has implemented the 3Rs principles by their adoption in certain WHO written standards (e.g. nonclinical evaluation, lot release), establishing well-characterized cell banks (e.g. Vero, MRC-5) that allow replacing primary animal cells for vaccine production, and coordinating international collaborative studies on the suitability of reference standards and reagents. WHO also updates written standards for vaccines based on available state-of-art knowledge and scientific evidence. The concept of consistency of production has been introduced for final lot release testing for a number of vaccines in WHO written standards and implementation of the concept has the potential to reduce animal use worldwide. The recently developed WHO guidelines on independent vaccine lot release encourage the national control laboratories to (1) apply 3Rs principles to minimize the use of animals and (2) to pursue mutual recognition or collaborative agreement to accept animal testing performed in the exporting country's national control laboratory.

Models predict that immunizing as few as 20% of school children, important transmitters of influenza, will reduce influenza-related illness in the elderly. We evaluated the potential herd immunity during three influenza seasons, 2005-2006, 2006-2007 and 2007-2008, which followed the immunization of > 40% of school children in Knox County (KC), TN, with live, attenuated influenza vaccine. Individual-level demographic, health status and health service utilization information about KC residents > 65 years and those residing in the 8 surrounding counties was obtained from the United States Medicare Program's administrative data. Influenza seasons were identified based on virus isolation. Pneumonia and influenza (P&I) hospitalization rates per 1,000 were compared between the elderly residing in the two areas for the three influenza seasons, and the 3 prior seasons. Differences-in-difference multivariate analysis allowed us to estimate the effect of the school-based immunization program on P&I hospitalization rates simultaneously adjusting for other important individual-level covariates. The age-adjusted rates among the KC residents were significantly lower, 4.62 and 6.02 versus 6.54 and 7.58 than in the residents of the comparison counties during the first two intervention seasons, p = 0.001 and 0.037, respectively, but not in the third. However, after adjusting for the traditionally lower rates of P&I hospitalization in the comparison counties, as well as for the other covariates, we were not able to demonstrate a statistically significant effect of the vaccination program in reducing the rates in either group of the elderly. The impact of the covariates was as expected. Those associated with increased P&I hospitalization rates were increasing age, lower income, poorer health status, prior hospitalization (particularly for P&I), and high prior use of physician services. Influenza immunization of an elderly person reduced his/her probability of being hospitalized for P&I. In conclusion, Immunization of > 40% of school children did not result in a reduction of P&I hospitalization rates among the elderly. We believe that the failure to show an impact was likely due to the high level of immunization among the elderly (> 60%). Administration of influenza vaccine to children as a way to protect the elderly in situations where vaccine supplies are limited or the elderly are not accustomed to receiving influenza vaccine may still be appropriate.

Aerosol vaccination via the mucosa targets an epithelium critical to host defence against inhaled pathogens, potentially avoids needle injection, and provides an exciting opportunity in the development of stable dry powder vaccine formulations. Specialised cells in the mucosa are able to take up and guide antigens directly to immune cells. In contrast to soluble antigen formulations, particles with antigen also provoke a local sIgA mediated immune response before being presented to the systemic immune system. In this study, particles containing the model antigen BSA and chitosan as stabiliser with adjuvant activity are produced by spray drying. The compatibility and uptake of these particles via the respiratory epithelium is determined in vitro on Calu-3 cells. The in vitro deposition studies are performed in a nasal cast made from CT scan data using a novel nasal dry powder device. The deposition profile is optimised by the use of interactive mixtures with a low separation capacity. The spray drying process results in spherical particles with a size in the low micrometer range (x50 3 μm), which are well tolerated when administered to the cells and which are readily taken up. As the particles have to be big enough to be retained in the appropriate place in the respiratory tract (e.g. the nasal cavity) to be taken up efficiently, the primary particles are too small. Deposition studies show a high fraction of almost 56% transiting the nose and being capable of inhalation. This fraction can be reduced by utilising an interactive mixture with a carrier, where only 5% of the antigen carrying particles leave the nasal cavity. Particulate vaccine formulations are a promising formulation approach for mucosal vaccination targeting the nasal mucosa. With small antigen carrying particles immobilised on carrier particles, the antigen is delivered exclusively to the nose.