The origin of lyophilization of vaccines for mass immunization has a very interesting history. The initial advent of this technology as it relates to current concepts was based on enhanced stability, storage and ambient conditions, shipping at room temperature, ease of administration and distribution.
The first known documented evidence of freeze drying of a vaccine relates to that of a small pox vaccine in early nineteenth century. Initial efforts to form a "dry powder" by air drying of vaccine components laid the foundation for subsequent advances in the dehydratation by lyophilization. The first freeze dried formulation for a small pox vaccine was published in 1909. Subsequently, both the bacillus Calmette-Guérin (BCG) and the small pox vaccine were formulated as a multidose dried powder.
"Dry Vax" small pox vaccine was launched in 1940's for mass immunization in several countries. This was one of the first commercial launches of a sterile formulation for parenteral use. The 100-dose single vial composition also contained phenol as a preservative.
Leslie Collier is credited with helping develop a viable vaccine that led to the eradication of smallpox. Collier's major contribution was in perfecting the art of freeze drying method of producing the vaccine for mass use. Dr. Collier developed the method of freeze drying of vaccinia virus that was subsequently adapted to larger-scale freeze dried vaccine production in many laboratories throughout the world.
This was a very critical step in making the vaccine available for mass distribution, as earlier vaccine required refrigeration. The original method of freeze-drying of smallpox vaccine employed by Camus and others was suboptimal. Phenol was added to the freeze-dried vaccine as an antimicrobial agent. Despite its effectiveness as an antimicrobial agent, phenol also damaged the virus. This opened the door for researchers looking for an alternative excipient to add to the composition for a long shelf life. Collier added a key component "peptone" to the process of freeze-drying. The powder was reconstituted with a solution of glycerin. This modified freeze-drying process to a large extend was the main driver in leading the global eradication fo smallpox. Simillar efforts in Europe were also demonstrated effectively with BCG freeze-dried composition. This further led to the acceptance of BCG in endemic countries very quickly.
Despite the success with small pox and BCG, most toxoids and adjuvants used from 1930 onwards did not succeed in being freeze-dried. The primary reason attributed to their failure was adsorption on mineral salts. Aluminum hydroxide and aluminum phosphate, the two primary salts for adsorption with diphtheria and tetanus toxoid, were not compatible with the dehydratation approach as significant aggregation of the mineral salts was seen upon freezing and the loss of potency in vivo of toxoids upon freezing was observed.
Another vaccine that has made a major impact on providing postexposure protection in endemic countries using a freeze-dried vaccine, is the rabies vaccine. A lyophilized rabies vaccine was developed in the 1960's that led to a longer shelf life and aided a better utilization in a postexposure setting in the developing countries.
The largest-scale commercial application of a lyophilized vaccine formulation is credited to this date in erradicating small pox and better utilization of BCG and rabies vaccine specially in the developing world.
Original text: Lyophilized Biologics and Vaccines: Modality-Based Approaches
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