Multivalent Stable Vaccine Composition and Methods of Making Same

Abstract

Stable immunogenic composition capable of eliciting a robust and durable immune response yielding a measurable increase in neutralizing antibodies at least 200 days post-administration, comprising at least one antigen consisting of a ribosome inactivating protein and at least one antigen comprising a toxin derived from bacterial spores. Method making and using a stable immunogenic composition capable of eliciting a stable immune response yielding a measurable increase in neutralizing antibodies at least 200 days post-administration, comprising providing an immunogenic composition comprising at least one antigen comprising a ribosome inactivating protein and at least one antigen comprising a toxin derived from bacterial spores and administering the immunogenic composition to an individual.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application No. 62 / 022,353, filed on Jul. 9, 2014, the contents of which are hereby incorporated by reference herein.FIELD OF THE INVENTION[0002]The invention relates to stable immunogenic compositions comprising more than one antigen and conferring increased immunity to an individual. The invention also related to methods of making and using the stable immunogenic compositions described herein.BACKGROUND OF THE INVENTION[0003]Vaccination is an important tool for handling health care programs both in developed and developing nations. The number of recommended vaccines has increased significantly in recent years against individual infections. Presently, the schedule of infants and children may require more than 24-25 separate shots of vaccines for effective immunization against life threatening diseases.[0004]The majority of vaccines currently in development belong to a specific class of subunit vaccine ...

AI Technical Summary

Benefits of technology

[0061]The present invention provides for a stable immunogenic composition capable of eliciting a robust and durable immune response yielding a measurable increase in neutralizing antibodies at least 200 days post-administration, comprising at least one antigen consisting of a ribosome inactivating protein and at least one antigen comprising a toxin derived from bacterial spores. Optionally, the immunogenic composition comprises a first antigen comprising a ribosome inactivating protein and a second antigen comprising a toxin derived from bacterial spores. In an alternative embodiment, the composition yields a measurable increase in neutralizing antibodies to the first antigen comprising the ribosome inactivating protein. In another embodiment, the composition is capable of yielding a measurable increase in neutralizing antibodies to the second antigen comprising a toxin derived from bacterial spores. In yet another embodiment, the composition is capable of yielding a measurable increase in neutralizing antibodies to both the first and the second antigen. Optionally, the composition of the present invention elicits a measurable increase in neutralizing antibodies to the first antigen at least 200 days post-administration. Alternatively, the composition of the present invention elicits a measurable increase in neutralizing antibodies to the second antigen at least 200 days post-administration. In yet another embodiment, the composition of the present invention elicits a measurable increase in neutralizing antibodies to the first and the second antigen at least 200 days post-administration.

Problems solved by technology

However, due to complications associated with the preparation of such combination vaccines due to possible interaction between the antigens has always been a challenge before the scientific community.

Complications include immune interference when vaccine antigens are administered concurrently at the same site in the body, and instability of the antigens together in combinations, impeding the simultaneous development of protective immunity.

Combination vaccines, while greatly desired for ease of administration and increased compliance, pose difficulties in development due to factors including: physical and biochemical incompatibility between antigens and other components, immunological interference and stability.

In a combination vaccine, a specific adjuvant may reduce the activity of one antigen and excessively increase the reactivity of another antigen.

All these potential interactions between vaccine components can negatively effective vaccine potency reducing the immunogenicity of the vaccine.

However, there is also the concomitant risk of reducing the vaccine's efficacy.

However, the number of adjuvants with acceptable efficacy and safety profiles is limited, and these proprietary molecules / compounds are in the hands of a few companies, as is most of the formulation expertise.

The use of aluminum adjuvants is thus fostered by the fact that the record of safety of newer formulations cannot match the long term acceptability of aluminum adjuvants in human vaccines.

Overall, this has amounted to a lack of advanced adjuvants that can be applied to vaccine development, coupled with the fact that several of the most advanced adjuvant formulations / compounds are the property of large pharmaceutical companies.

Aluminum adjuvants are considered relatively weak, effective in generation of neutralizing antibodies against certain bacterial antigens, but relatively ineffective at inducing cellular immune responses.

However, a solution pH that provides optimal protein stability, may not allow for appropriate binding of the vaccine to adjuvants.

However, a variety of exploratory formulations to enhance vaccines have been developed as more potent alternative to aluminum-salts adjuvants, but are not currently available in FDA-licensed human vaccines.

Very little data is available on the storage of dried vaccines under elevated temperature conditions, as most of the attempts to generate dried vaccines have been to obtain inhalable powders or preparations able to survive moderate excursions in temperature.

Although a moderate amount of stability can be achieved with liquid suspension vaccines, it is not likely that all stability parameters can be met for longer storage periods that are required for vaccines to be stockpiled and distributed.

In the case of protein immunogens that are adsorbed to aluminum adjuvant crystals, the measurement of function and other parameters in vitro is correspondingly more difficult, since protein may be sequestered and difficult to remove for analysis.

Thus, function can only be tested by immunogenicity and protection studies.

These studies demonstrated the difficulty in identifying a pre-lyophilization solution pH that confers adequate physical and chemical stability to the proteins studied during lyophilization and storage.

Protein aggregation was minimized following lyophilization from a solution at pH greater than 6, although, deamidation occurred at an unacceptably high rate.

However, Roser et al., while disclosing prevention of gross particle aggregation, did not disclose the importance of freezing rate of a particulate suspension or other factors critical to control and maintain pre-lyophilization particle size and protein structure in an aluminum-salts containing vaccine in the presence of trehalose.

The mixing of antigenic components prior to administration from different vials results in the diminishment of the antibody titer against any particular antigen owing to interference of antigenic interactions.

It also specifies that, antigenic competition in such multivalent vaccines often results in a diminished response to certain individual antigens.

The patent application recognizes an inherent problem of mixing of lyophilized vaccines with liquid vaccines which represents supplementary constraint for the practitioner and involves a possibility of the same being carried out in a poor fashion.

It also recognizes that the usage of multi-compartment syringes having separate chambers for liquid and lyophilized vaccines is too difficult to execute and no reduction in production costs (and by extension, no reduction of the cost of immunization) of the vaccine is possible.

Ricin is a highly toxic, naturally occurring lectin (a carbohydrate-binding protein) produced in the seeds of the castor plant Ricinus communis.

Ricin is thought to be a bioterror threat because of its stability and high potency as well as the large worldwide reservoir created as a by-product of castor oil production.

Exposure to ricin results in local tissue necrosis, and general organ failure leading to death within several days of exposure.

Ricin is toxic by all routes of exposure, but is especially toxic by the aerosol route, resulting in necrosis of lung epithelia within hours of exposure, multifocal hemorrhagic edema and death within 24-36 hours, with an estimated aerosol LD50 of 5-8 micrograms per kilogram of body weight (0.4 mg-0.64 mgs for an average adult).

Antibodies to ricin, and more specifically the A chain of ricin, can prevent morbidity and mortality, if given passively prior to or very shortly after exposure, but the therapeutic window of opportunity post exposure is likely to be hours, prior to irreversible toxicity, lowering the probability of successful and effective post-exposure intervention.

Equally important, non-neutralizing monoclonal antibodies do not confer protection.

The levels of anti-RiVax™ Ab were neither robust nor long lasting.

Moreover, levels of toxin-neutralizing Ab were also extremely low in RiVax™-immunized individuals.

Because the spores are robust and contagious, anthrax is considered a Category A bioterror threat.

After infection in the bloodstream, the bacteria synthesize a complex series of toxin components that make up anthrax toxin, resulting in overwhelming toxemia that causes shock and organ failure.

Only a few inhaled spores can cause inhalational anthrax poisoning.

Once the toxin has entered the bloodstream, antibiotics are ineffective, and only toxin-specific therapy is effective.

These products are currently stockpiled under environmentally controlled (cold chain) refrigerated storage conditions until those unpredictable events would occur, imposing huge logistical demands on maintaining the stockpile for those targeted interventions.

Limitations noted in the development of recombinant PA based vaccines have been rapid deamidation of rPA and loss of potency of liquid aluminum adsorbed vaccine.

Therefore, the overall potency and related immunological correlates of effectiveness for any PA vaccine are still undeveloped.

Upon exposure to acidic conditions, however, the complexes do not undergo membrane insertion or pore formation, and are not able to translocate the LF and EF into the cytosol.

Thus, toxicity is completely blocked.

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