Multivalent vaccine composition
Inventors
DHERE, Rajeev Mhalasakant • Pisal, Sambhaji Shankar • ZADE, Jagdish Kamalaji • SABALE, Rajendra Narayan • KADAM, Ravindra Bapurao • KAMBLE, Abhijeet Sanjeev • Jiang, Baoming • Glass, Roger
Assignees
Serum Institute of India Pvt Ltd • US Department of Health and Human Services
Publication Number
US-11235054-B2
Publication Date
2022-02-01
Expiration Date
2037-08-24
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Abstract
Stable, immunogenic combination vaccine(s) comprising a mixture of antigens for prevention and prophylaxis of infections caused by Rotavirus, Poliomyelitis virus, Haemophilus influenzae, Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis and Hepatitis B virus. A multivalent combination vaccine comprises i) significantly dose-reduced Salk-IPV or Sabin-IPV (IPV) antigens prepared by methods of formaldehyde inactivation and alum hydroxide adsorption resulting in maximum D-antigen recovery; ii) Injectable heat inactivated Rotavirus antigen(s) providing broad cross-protective immunity among human rotavirus strains; iii) Hib PRP-carrier protein conjugate having improved stability and immunogenicity; iv) whole cell pertussis antigen with improved immunogenicity and stability; and v) Homogenous fractions of Diphtheria and Tetanus toxoids. Such stable and immunogenic vaccine compositions are made by i) individually adsorbing dose reduced IPV, IRV antigens on alum hydroxide and keeping other antigen(s) unadsorbed or adsorbed on alum phosphate, alum hydroxide, or a combination thereof; and ii) using an order of addition of antigens during blending.
Core Innovation
The invention relates to stable, immunogenic multivalent combination vaccines comprising a mixture of antigens for prevention and prophylaxis of infections caused by Rotavirus, Poliomyelitis virus, Haemophilus influenzae, Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, and Hepatitis B virus. The vaccine particularly comprises significantly dose reduced Salk or Sabin IPV antigens prepared using improved formaldehyde inactivation in presence of TRIS buffer and alum hydroxide adsorption for maximum D-antigen recovery, injectable heat inactivated Rotavirus (CDC-9) antigens providing broad cross-protective immunity, Hib PRP-carrier protein conjugate with improved stability made via a novel conjugation process, whole cell pertussis antigen added later in blending to minimize degradation, and homogeneous fractions of diphtheria and tetanus toxoids purified by gel permeation chromatography.
The method of preparation includes individually adsorbing the dose reduced IPV and IRV antigens on alum hydroxide, while other antigens are either unadsorbed or adsorbed on aluminum phosphate, aluminum hydroxide, or combinations thereof, and blending the antigens in a specific order at controlled temperature with stabilizers. This composition provides a stable, immunogenic all-liquid multivalent vaccine suitable for developing countries with reduced IPV dosage and broad rotavirus protection, overcoming antigenic interference and stability issues prevalent in current combination vaccines.
The problem being solved addresses the challenges in current vaccines including the high production costs and antigen loss of IPV when produced using conventional phosphate buffers, the limited cross-protection and modest efficacy of existing oral rotavirus vaccines especially in low-income countries, and stability issues with Hib and whole cell pertussis antigens in combination formulations. Furthermore, the invention addresses the need for affordable multivalent vaccines that reduce the number of shots, ensuring improved compliance and cost-effectiveness, while maintaining or improving individual antigen immunogenicity and stability in multi-antigen formulations.
Claims Coverage
The patent claims encompass multiple inventive features related to vaccine compositions and manufacturing processes. Key independent claims cover the multivalent vaccine composition with dose reduced IPV and IRV antigens, specific adsorption on aluminum adjuvants, purified toxoids, and novel stabilization and blending techniques.
Dose reduced inactivated polio virus antigen formulation
The vaccine includes dose reduced inactivated polio virus antigens derived from Salk or Sabin strains, with specific dose compositions of Type 1, Type 2, and Type 3 D-antigen units listed (e.g., 5-16-10, 8-2-5 units), adsorbed on aluminum hydroxide adjuvant with controlled Al3+ concentration and adsorption percentage to maximize D-antigen recovery and potency.
Injectable heat inactivated rotavirus antigen with aluminum hydroxide adsorption
The rotavirus antigen comprises injectable heat inactivated rotavirus strains (e.g., CDC-9, CDC-66), adsorbed onto aluminum hydroxide adjuvant at specified Al3+ concentrations, ensuring high adsorption (>70%) and antigen integrity for broad cross-protection.
Purified diphtheria and tetanus toxoids adsorbed on aluminum phosphate
Diphtheria and tetanus toxoids are purified using gel permeation chromatography methods with specific resins to yield high monomeric content (at least 80%), and adsorbed onto aluminum phosphate adjuvant to enhance immunogenic stability.
Pertussis antigen selection and improved inactivation methods
Pertussis antigen can be acellular with specific protein components or inactivated whole cell pertussis derived from specific Bordetella pertussis strains, produced by improved inactivation methods devoid of thimerosal to maintain potency and reduce reactogenicity.
Hib PRP-carrier protein conjugate produced by cyanylation chemistry
The Hib antigen is a PRP polysaccharide conjugated covalently to carrier proteins (e.g., CRM197, diphtheria toxoid) using cyanylation reagents such as CDAP, yielding conjugates with controlled saccharide:protein ratios and minimal free PRP content to ensure stability and immunogenicity.
Hepatitis B surface antigen individually adsorbed on aluminum phosphate
Hepatitis B surface antigen (HBsAg) is recombinantly produced and individually adsorbed on aluminum phosphate adjuvant to optimize antigen stability within the multivalent vaccine.
Vaccine composition with specific excipients and preservatives
The combination vaccine includes preservatives such as 2-phenoxyethanol and pharmaceutically acceptable excipients like sugars, amino acids, and buffers (e.g., histidine) to maintain pH, stability and immunogenic potency.
Specific multivalent vaccine compositions with defined antigen doses
Bivalent, hexavalent, and heptavalent formulations include precise antigen dose ranges for IPV (types 1-3), IRV, D, T, wP, Hib conjugates, and HBsAg, maintaining total aluminum content below specified limits to ensure safety and efficacy.
Manufacturing processes involving individual adsorptions and blending order
Process claims define steps such as individual adsorption of IPV and IRV antigens on aluminum hydroxide, adsorption of D and T on aluminum phosphate, blending with controlled pH and temperature, subsequent addition of wP antigen and Hib conjugate, along with stabilizers and excipients, to produce stable, immunogenic liquid combination vaccines.
Stabilization of Hib conjugate and whole cell pertussis antigen by formulation sequence
Use of a novel conjugation process for Hib PRP-carrier protein conjugate blended at low temperature with stabilizers reduces free PRP release and improves immunogenicity. The whole cell pertussis antigen is added late in the blending to minimize hydrolysis-based degradation and maintain potency.
The claims comprehensively cover the composition of multivalent vaccines incorporating dose reduced IPV, injectable heat inactivated rotavirus antigen, purified toxoids, stabilized Hib conjugates, pertussis antigens, and Hepatitis B surface antigen, along with the methods of manufacturing using specific adsorption and blending sequences. This ensures the production of stable, immunogenic, and cost-effective combination vaccines suitable for broad immunization programs.
Stated Advantages
Significantly reduced dosage of IPV antigen allows lowering of production costs while maintaining immunogenicity.
Injectable heat inactivated rotavirus antigen provides broad cross-protective immunity among diverse rotavirus strains.
Hib PRP-carrier protein conjugate prepared via novel conjugation process and blended with stabilizers ensures improved stability and immunogenicity with minimal free PRP release.
Whole cell pertussis antigen added at a later stage minimizes hydrolysis based degradation resulting in improved antigen stability and immunogenic potency.
Purification of diphtheria and tetanus toxoids by gel permeation chromatography yields homogeneous fractions with high monomer content, reducing adverse reactions.
The multivalent vaccine simplifies immunization schedules, improves compliance by reducing number of injections, and reduces delivery costs for developing countries.
Stability of multivalent vaccines is enhanced through controlled adsorption on aluminum adjuvants and optimized blending order of antigens.
Documented Applications
Prevention and prophylaxis of infections caused by poliomyelitis virus.
Prevention and prophylaxis of infections caused by rotavirus to reduce incidence of severe acute diarrheal disease in infants and children.
Prevention and prophylaxis of infections caused by Haemophilus influenzae type b.
Prevention and prophylaxis of infections caused by Corynebacterium diphtheriae (diphtheria).
Prevention and prophylaxis of infections caused by Clostridium tetani (tetanus).
Prevention and prophylaxis of infections caused by Bordetella pertussis (whooping cough).
Prevention and prophylaxis of infections caused by Hepatitis B virus.
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