Methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
Inventors
DHERE, Rajeev Mhalasakant • Pisal, Sambhaji Shankar • ZADE, Jagdish Kamalaji • SABALE, Rajendra Narayan • Malviya, Hitesh Kumar • MAHOR, Sunil • JOSHI, Chetan Vilasrao
Assignees
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Publication Number
US-11793869-B2
Publication Date
2023-10-24
Expiration Date
Abstract
The present invention is directed to improved methods of Enterovirus inactivation by formaldehyde in presence of tromethamine buffer resulting in maximum recovery of D-antigen. Subsequent adsorption of said sIPV on aluminium hydroxide provides significantly dose reduced sIPV compositions.
Core Innovation
The invention relates to dose reduced Inactivated Polio vaccine (IPV) compositions and related combination vaccines in which IPV antigens are produced by formaldehyde inactivation in a non-phosphate buffer selected from TRIS, TBS, MOPS, HEPES and bicarbonate. It addresses D-antigen loss during formaldehyde inactivation that is associated with phosphate buffer driven aggregation, which reduces preservation of epitopes and leads to reduced D-antigen recovery post inactivation.
To solve this, the disclosure uses formaldehyde inactivation in a non-phosphate buffer to prevent or reduce aggregation of Enteroviral poliovirus particles and thereby reduce D-antigen losses post inactivation by 8 to 10 fold as compared to inactivation in phosphate buffer. The non-phosphate buffer concentration is described as present at 30-70 mM, with the goal of achieving reduced aggregation and reduced D-antigen losses while maintaining the inactivated polio virus antigen.
The invention further enables dose sparing of IPV in multi-antigen formulations by adsorbing the inactivated IPV antigen onto an aluminium salt of hydroxide (Al(OH)3) having a percentage adsorption of at least 90%. With this adsorption approach, the disclosure reports significant IPV dose sparing in combination vaccine compositions, including about 8-fold for Sabin Type 1 and about 3-fold for Sabin Type 3.
Claims Coverage
The independent claims cover four inventive features relating to dose-reduced IPV and combination vaccines.
Dose reduced IPV multi-antigen composition with non-phosphate formaldehyde inactivation and Al(OH)3 adsorption
A dose reduced Inactivated Polio vaccine (IPV) composition comprising diphtheria toxoid (D), tetanus toxoid (T), whole cell pertussis (wP), hepatitis B virus surface antigen (HBsAg), Haemophilus influenzae b PRP-Carrier protein conjugate (Hib), and an inactivated polio virus antigen selected from IPV Type 1, IPV Type 2 and IPV Type 3 at specified dose ranges, wherein the IPV antigen is produced by formaldehyde inactivation in a non-phosphate buffer selected from TRIS, TBS, MOPS, HEPES and bicarbonate, and wherein the inactivated polio virus antigen is adsorbed onto aluminum salt of hydroxide (Al(OH)3) having a percentage adsorption of at least 90%.
Manufacturing process using aluminium adsorption on different aluminium salts with staged pH adjustments
A process of manufacturing a dose reduced Inactivated Polio vaccine (IPV) composition wherein the IPV antigen is produced by formaldehyde inactivation in a non-phosphate buffer selected from TRIS, TBS, MOPS, HEPES and bicarbonate, and the process comprises adsorbing the IPV bulk individually on aluminium hydroxide, adsorbing D, T and HBsAg on aluminium phosphate, blending the mixture by agitation, blending the IPV/aluminium hydroxide content with the mixture, adding an inactivated wP antigen/acellular pertussis antigen and a stabilizer, adding Hib antigen, and adjusting pH.
Purify in phosphate buffer, exchange to non-phosphate buffer, stabilize, and formalin inactivate with reduced D-antigen losses
A method for producing a composition comprising Enteroviral poliovirus particles wherein the method comprises purifying the Enteroviral poliovirus particles in a medium comprising a phosphate buffer; exchanging the phosphate buffer for a non-phosphate buffer selected from TRIS, TBS, MOPS, HEPES or bicarbonate; stabilizing the purified and buffer-exchanged particles; and inactivating the particles by adding formalin, wherein aggregation is prevented or reduced and the D-antigen losses are reduced post inactivation by 8 to 10 fold as compared to inactivation in phosphate buffer.
Combination vaccine with defined vaccine portion and non-phosphate formaldehyde-inactivated IPV
A combination vaccine comprising a vaccine portion and a buffer portion, wherein the vaccine portion consists essentially of diphtheria toxoid (D), tetanus toxoid (T), whole cell pertussis (wP), hepatitis B virus surface antigen (HBsAg), Haemophilus influenzae b PRP-Carrier protein conjugate (Hib), and an inactivated polio virus antigen selected from IPV Type 1, IPV Type 2 and IPV Type 3 at specified dose ranges, wherein the IPV antigen is produced by formaldehyde inactivation in a non-phosphate buffer selected from TRIS, TBS, MOPS, HEPES and bicarbonate.
Across the independent claims, the coverage centers on dose-reduced IPV and combination vaccines where IPV is inactivated by formaldehyde in a non-phosphate buffer to reduce aggregation and D-antigen losses, and where the inactivated IPV antigen is integrated into multi-antigen formulations via aluminium salt adsorption, particularly adsorption onto Al(OH)3 with at least 90% adsorption.
Stated Advantages
Reduced D-antigen losses post inactivation by 8 to 10 fold as compared to inactivation in phosphate buffer.
Prevention or reduction of aggregation of Enteroviral poliovirus particles.
High IPV adsorption onto aluminium hydroxide (Al(OH)3) with a percentage adsorption of at least 90%.
Significant IPV dose sparing in combination formulations, including about 8-fold for Sabin Type 1 and about 3-fold for Sabin Type 3.
Documented Applications
Dose-reduced inactivated polio vaccine (sIPV) and related combination formulations including diphtheria toxoid (D), tetanus toxoid (T), whole cell pertussis (wP), hepatitis B virus surface antigen (HBsAg), and Haemophilus influenzae b PRP-Carrier protein conjugate (Hib).
A method for producing Enteroviral poliovirus particle compositions using phosphate buffer purification followed by buffer exchange to a non-phosphate buffer and formalin inactivation with reduced D-antigen losses.
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