i Vaccine, Vol. 16, No. 19, pp. 1780-1787, 1998 0 1998 Published by Elsevier Science Ltd. All rights reserved Printed in Great Britam zyxwvuts PII: SO264-410X(98)00168-6 0264-410X198 $iS+O 00 zyxwvutsr Deceptive imprinting: a cosmopolitan strategy for complicating vaccination Peter L. Nara and Robert Garrity The need to develop effective vaccines against both chronic-active and annually re-occurring viral, bacterial and parasitic pathogens are considered some of the most important global vaccine objectives of the 21st Century. This is highlighted by the expanding nature of the HIV-l pandemic (some 1400 new infections every day world- wide), the increasing number of persons infected with viruses, bacteria and parasites who will need repeated, expensive, somewhat toxic and long-term chemotherapy, the increasing resistance of insects to insecticides, antibiotic-resistant bacteria, increasing levels of sexually transmitted diseases and the more basic need to develop new vaccine technologies against a disease for which conventional vaccine strategies appear to have fallen short of their mark. A striking disparity exists between the small number of diseases currently prevented by available vaccines, and the many infectious diseases for which no vaccine is available. Failure of many of these vaccines may be attributed to a lack of understanding of how to circumvent complex immune evading strategies that have evolved to favour persistent pathogenic infections. In general, HIV-1 and other chronic-active or annually re-occurring viral (i.e. Hepatitis C, influenza, and rhinoviruses), parasitic (i.e., malaria) and bacterial (i.e., Neisseria gonorrhea, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Strepto- coccc~s sp. etc.) pathogens exhibit one or more of the following properties: genetic instability during replication within and between hosts; induction of robust immune responses which convey either type-restricted, limited, or nonprotective immunity; mediate immune enhancement; result in immune dysregulation and problems associated with memory; and finally, preclude the establishment of durable immunity during a convalescent stage. Interest- ingly, these responses in outbred populations are directed at immunodominant epitopes that appear to have little or nothing at all to do with protection. At an immunochem- ical level they can be protein, glycoprotein or carbo- hydrate and exhibit one or more of the following characteristics: high local charge, high degree of hydro- philicity, high degree of molecular freedom, redundant steric-specific presentation, and amphipathic helix struc- ture. This ‘natural’ immunodominance has been recog- nized for a very long time and in the parasite arena was suggested as early as 1972 as bein 8 acting as a ‘smoke screen’ to the immune system Immunodominant epitopes are known to suppress a primary immune response to other antigenic determinants by a number of mechanisms and will be discussed where they apply throughout the text. DISPROPORTIONATE ANTIGENICITY Introduction of foreign antigens into the host either by vaccination or infection in many cases leads to the production of specific antibody’. Depending on the nature Biological Mimetics Inc., Frederick, MD 21701, USA 1780 Vaccine 1998 Volume 16 Number 19 of the immunogen and the various pathways leading to B-cell activation, the clonality of the response is ultimately evoked by a given epitope. In most cases, antigens repre- sent a broad array of epitopes, and consequently the antibody response is chemically heterogeneous and antigenically specific. Some multi-determinant antigens (i.e. albumin, hen egg white lysosyme, HBV epitope Cro Lac-gp41, etc.) result in an unequal response to some epitopes (reviewed in Ref. ‘). Given the potentially large B-cell repertoire in any given host, selective recognition of specific epitope by a limited population of B cells needs explanation to deter- mine whether this restriction is due to the immunogen itself, or to host factors involved in its selection. Some antigens induce a less variable response, for example: certain carbohydrate antigens, antigens with structural/ functional homology to self (Table I), other antigens displaying a limited, highly ordered, or redundant number of immunodominant cross-reactive sites, more often with a unique steric presentation (i.e., streptococcal group A-variant cell wall)“. For example, an animal immunized with one of these antigenic determinants and later exposed to a different, but structurally similar determinant responds to this second determinant by initially producing antibody (sometimes with a higher affinity) to the original antigen, a phenomena referred to as OAS (Table I). In many cases, depending on the antigen concentration, continued boosting with the first or second Ag also elicits a normal primary response to the second antigen2. Studies on influenza in the early 1990s suggested that early primary B cell response to influenza in Balb/c mice displayed some unusual properties. It was observed that the early primary B cell response to the influenza virus NPR/8/344 (PR8) haemagglutinin (HA) is dominated by B cells which utilize a single Vx gene in association with one of two closely related VH genes. These cells interest- ingly do not expand into a functional memory pool’. In addition, it was observed by others that these immuno- dominant responses were directed at and focused on limited regions of the HA molecule during a primary viral zyxwvuts Table 1 B-cell abnormalities during HIV-l infection” 1. 2. 3. 4. 5. 6. Infection with HIV-1 triggers a strong/sustained antibody response-approximately lo-50% of peripheral IgG-secreting B cells are HIV-l specific. Evidence for high-frequency of pre-existing HIV-l reacting B cells in normal seronegative individuals45-50% in both adults (l/16200-49000) and newborns (l/l 1800-26600). Evidence for abnormal selection of the B cell repertoire: (1) 26% show overt IgG monoclonal populations demonstrating cross-reactivity with p66 pol and p55 gag. Skewing of K/L ratios, shared idiotypes to different HIV-l components. Gpl20 acting as a natural ligand for VHIII gene product-B cell superantigen; Structural similarities of gp120 and IgH variable and FW region segments. “Reviewed in Ref. 4