See also antibody production
Immunogen dosage and route of administration also affect immune response. A dose may be too small or too large to induce an immune response. An insufficient dose will not stimulate an immune response either because it fails to activate enough lymphocytes or because certain ranges of low doses can actually induce a state oftolerance in some cases. An excessively high dose can also induce tolerance. A single dose of most experimental immunogens will also not induce a strong response. Repeated administration or “boosters” over a period of weeks is required to stimulate a strong response. Experimental immunogens generally are administered parenterally(routes other than the digestive tract) as by intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes. Antigen administered intravenously is first carried to the spleen, whereas antigen administered subcutaneously moves first to local lymph nodes.The route of antigen injection determines which immune organs and cell populations will be involved in the response.
Immunization with Multiple Antigens
A potential vaccine against a variable pathogen such HIV whoucld include a variety of antigens to produce an immune response to the variants of the pathogen to which an individual may become exposed (Maksyutov, US 2006/0153865).
Repetitive, multiple site immunization strategy (RIMMS):
Kilpatrick “Rapid development of affinity matured monoclonal anitobides using RIMMS” Hybridoma, 16(4), 1997, discloses RIMMS immunization of antigen into several subcutaneous sites, proximal to draining lympodes of mice over the course of 7-11 days.
Immunization with plurality of antigens, generally
Sawyer (US2005/0181483) discloses methods for producing monoclonal antibodies by introducing at least one antigen (e.g., multiple antigens) into an animal, recovering antibody producing cells, generating immotalized cell line and screening the supernant against a protein chip to select a monoclonal antibody that binds to the candidate antigen. The animal may be immunised with the antigen(s) via more than one of a number of possible routes (e.g., intrasplenically, intravenously, intraperitoneally, intradermally or subcutaneously). For example, some of the purified antigen(s) may be injected intraperitoenally and the rest subctaneously.
Stinchcomb (US 2010/0303860) discloses a singel dose vaccine against dengue virus that can include one or more dengue virus serotpye(s). In one embodiment, a subject is adminsitered at a seaprate site from the first injection, for example next to or in a separate anatomic site.
Zhang (US2004/0111757) discloses a method for producing a plurality of monoclonal antibody by administering a plurality of antigens or a cellular immunogen made up of a cell population expressing a plurality of antigens to a single animal to induce an immune response agaisnt the plurality of antigens.
Administration of plurality of antigens, each antigen administered at distinct anatomical site
Deem (US2006/0246081) discloses a method of administering to a subject a plurlity com positions, each composition being adminsitered to a different site of the subject, wherein each site is, or substantially drains to, an anatomically distinct lymph node(s). Each composition includes at least one antigenic molecule having one or more epitopes of the same infectious agent or a strain thereof. The method is advantageous in that it helps against immunodominance where an immune response is elicited against a particular infectious agent, often directed against only a limited number of epitopes or even to a singel epitopoe. Such a narrow immune response to a few immunodominant epitopes offers poor protection against subsequent infection by a mutated form or by different strains of the original infectious agent.
Chowdhury (US 14/380,128, published as US20150110802)) discloses a method of proudcing a plurality of antibodies in a single animal by immunizing with a plurality of antigens where each antigen species is deliverd to the animal at an anatomically distinct location.
Linking of Antigens on single polypeptide
Multiple antigen peptide system (MAPs):
MPS system is a novel approach for antibody geenration using B eptiopes and T helper epitopes which are linked tandemly on a multi-branched lysine core. ((Yuang, Vaccine, 15(4), pp. 377-386, 1997).
Boosters
Boosters with the Same Antigen:
The use of a prime boost immunization schedule is well known. For example, children typically receive a series of primary immunization up to the age of 15 months (e.g., a DTPa vaccine) and then receive booster doses aged between 4-6 years and beyond (e.g., a Tdap vaccine). Although the priming and boosting vaccines may differ in their precise composition (e.g., the antigen ratios differ in DTPa and Tdap vaccines) antigens used in the two vaccines are typically the same.
Boosters with Different Antigens:
Dormitzer, (US 13/125,526 and 14/219,196) discloses a immunization protocl that uses two or more different antigens which are administered in series or sometimes in combination where the first antigen elicits an efficient germline antibody response and the second antigen elicits an efficient and desired affinity maturation of the antibody response. The first antigen binds to the germline antiboy with greater affinity than to the affinity matured antibody and the second antigen binds to the affinity matured antiboy with greater affinity than to the germline antibody.
Wysocki (US5,641,488) disclsoes a method for producing antibodies of desired specificity by immunizing an animal with a first immunogen and then with a second immunogen wehre the second immunogen stiulates proliferation of a subpopulation of B cells which have undergone somatic hypermutation to produce antibodies specific to said chosen antigen. In one embodiment, Wysocki disclosing using “Ars” as a first antigen and “Sufl” as the second antigen and that the antibodies which are subsequently generated by immunization with Ars change their specificity to bind “Sulf”.
Ellenberger (“Recruiting memory B cells with changed antigenic Specificity” J. Immunol., 151, 1993, pp. 5272-5280) also teaches immunization with a first antigen (“Ars-KLH) which recruit and includ somatic mutations in canonical anti-Ars clones haivng acquired new antigenic specificities which were rescued with booster injections with a second related but different antigen (“Sulf-KLH).