Haemophlius Influenza

Haemophilus influenza, a gram negative coccobacilli, is a bacterial agent that causes disease globally. There are six serological types of of Haemophilus influenza, types a, b, c, d, and e. These separate types are determined based on the antigen structure of the capsular polysaccharides recognized by the host immune system. Haemophilus influenza type b (Hib) is one of the causative agents of bacterial meningitis, which is particularly prevalent in children under five years of age.

The symptoms associated with Hib infection are fever, lethargy, vomiting, and stiff neck.[17] Hib infection can be diagnosed by gram staining of the cerebrospinal fluid, by detecting capsular material, or by culturing Hib organisms on chocolate agar.[18]

Gram-negative stain of Haemophilus influenzae. Source: University of Minessota Medical School [20]

If infected, an individual can be treated with a variety of antibiotics, such as ampicillin, chloramphenicol, and rifampin, and with cephalosporins which have bacteriocidal activity and can cross the blood-brain barrier. [17,18] In terms of prevention of Hib infection, vaccines have played an important role in the reduction of disease cases. Dramatic evidence of the efficacy of the vaccine is apparent through several sources of data. For example, before 1988, when conjugate Hib vaccines were first introduced, Hib invasive disease was the most common cause of bacterial meningitis in children in the United States. Several years later, in the early 1990’s, a drastic reduction of greater than 95% was seen in the incidence of Hib invasive disease. [16] These stifling numbers raise interest in the function and form of such a vaccine.

Haemophilus influenza type b is transmitted through direct contact with mucousal fluid from an infected person or by contact with droplets from the nose and/or throat of that person.[18] The organism colonizes in the nasopharynx area and can penetrate the epithelium to produce a bacteremia where the organism has localized in many organs throughout the body.[18]

The immune response to such an infection as described above is mostly a humoral response. The major immunogenic factor present on Hib is the polyribosylribitol phosphate (PRP) capsule.[15]

Haemophilus influenzae genome. Source: NIH [21]

This capsule is a T-independent antigen and posseses characteristics of this sort of antigen. T-independent antigens generally are able to elicit a B cell response without contribution from T helper cells. The activated B cells secrete PRP-specific antibodies.[15] However this antibody response is weaker than humoral response elicited by T-dependent antigens.[15] Other distinguishing features of the T-independent B cell response are that no B memory cells are produced, the antibody response is primarily IgM dominant, and there is no affinity maturation of the antibodies.[14] These responses are shorter lived and less specific than responses elicited by T-dependent antigens.[14]

Knowledge of the immune response led to developments in the research on Hib vaccines. It is known that higher levels of PRP-specific antibodies are correlated to decreased risk of Hib invasive disease. [15] In the 1970’s polysaccharide vaccines derived from PRP were being developed in hopes that these vaccines would be able to elicit a response that produced bactericidal serum. These vaccines were shown to be 90% effective but only in children two years of age an older and only for a short period of time. [15] Further studies on these vaccines showed them to be variably effective. In the 1980’s, the conjugate vaccine approach was investigated based on findings of Goebel and Avery that a T-independent antigen could be changed to a T-dependent antigen by conjugation to a protein carrier. [14] The PRP protein was conjugated to a number of protein carriers including tetanus toxoid, diphtheria toxoid, mutant diphtheria toxin, and outer-membrane protein. [14] These vaccines are more advantageous than polysaccharide vaccines because they are immunogenic in very young children, even at two months of age, and they elicit longer lasting responses.[14] They also elicit a memory response which can be determined by rapidity of response to a challenge of pure PRP or by an increase in antibody avidity to pure PRP. The antibody responses to the conjugate vaccines are primarily IgG1 and some IgG2. Another advantage of the conjugate vaccines is that they influence herd immunity by reducing person-to-person spread of the organism by not only protecting the host from infection, but also by protecting the host from being a carrier. [14] These characteristics of the conjugate Hib vaccines explain the stifling drop of Hib invasive disease in the U.S.

Average annual incidence of Haemophilus influenzae invasive disease among persons of all ages, by country, United States, 1994-1995. Source: Kristine M. Bisgard. [21]