Combination vaccines with low dose of hib conjugate

Abstract

Provided herein are combination vaccines comprising antigens for protecting a subject against at least diphtheria, tetanus, pertussis and Hib, wherein: (a) the antigen for protecting against Hib is a conjugate of a Hib capsular saccharide; (b) the concentration of the Hib conjugate in the vaccine is <15 μg / ml; and (c) the Hib conjugate has never been lyophilised.

Description

[0001]All documents cited herein are incorporated by reference in their entirety.TECHNICAL FIELD[0002]This invention is in the field of combination vaccines, particularly those for protecting against diphtheria, tetanus, pertussis and H. influenzae type b (‘Hib’).BACKGROUND ART[0003]Combination vaccines including antigens for immunizing against diphtheria, tetanus, pertussis and Hib are known (‘DTP-Hib’ vaccines). Three such vaccines have been marketed under the names TETRAMUNE™ and QUATTVAXEM™ (which use cellular pertussis antigens ‘DTwP-Hib’) and INFANRIX-Hib™ (which uses acellular pertussis antigens ‘DTaP-Hib’).[0004]The inclusion of Hib-conjugate components in DTaP-Hib vaccines has been associated with reductions in the anti-Hib response [1, 2]. Furthermore, Hib-conjugates are unstable in aqueous media and cannot survive prolonged storage in this form [3]. For this reason, in combination vaccines that include Hib-conjugate antigens, it is common for the Hib component to be provi...

AI Technical Summary

Benefits of technology

[0043]An aluminium phosphate solution used to prepare a vaccine of the invention may contain a buffer (e.g. a phosphate or a histidine buffer), but this is not necessary. The aluminium phosphate solution is preferably sterile and pyrogen-free. The aluminium phosphate solution may include free aqueous phosphate ions e.g. present at a concentration between 1.0 and 20 mM, preferably between 5 and 15 mM, and more preferably about 10 mM. The aluminium phosphate solution may also comprise sodium chloride. The concentration of sodium chloride is preferably in the range of 0.1 to 100 mg / ml (e.g. 0.5-50 mg / ml, 1-20 mg·ml, 2-10 mg / ml) and is more preferably about 3±1 mg / ml. The presence of NaCl facilitates the correct measurement of pH prior to adsorption of antigens.

[0081]Where a saccharide antigen is used, it is preferably conjugated to a carrier protein in order to enhance immunogenicity.

[0104]A typical process for preparing bulk vaccine of the invention will add the Hib component to a mixture of the D, T and P components i.e. the DTP components are mixed prior to addition of the Hib component. This order of mixing allows the ionic strength and / or pH of the composition to be adjusted (e.g. pH<7) prior to addition of the Hib component in order to prevent adsorption to any aluminium adjuvant that may be present.

Problems solved by technology

Furthermore, Hib-conjugates are unstable in aqueous media and cannot survive prolonged storage in this form [3].

Hib-conjugate antigens are not cheap to produce, and there is concern that their cost will inhibit widespread use in developing countries, and so alternative strategies for Hib-conjugate use have been developed [4-6].

These vaccines must thus be provided in two separate containers (aqueous DTP in one, lyophilised Hib in the other), and this double container requirement imposes additional cost and logistical requirements at the packaging stage, the transport stage, the storage stage and the administration stage.

As the reduced-dose vaccines are intended to reduce cost and encourage distribution in the developing world then these additional requirements are significant disadvantages.

The requirement for a reconstitution step also means that there is a risk of error by the end user, a tendency towards non-standardised dosages, a risk of contamination of the mixed product and a need to train staff in the reconstitution procedure.

All of these problems frustrate the intended target market i.e. the developing world.

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