The fundamental problem with the use of specific serum antibody as an indicator of vaccine efficacy is that it only demonstrates a limited aspect of immune function. Also, this aspect of immune function has been shown to have an inconsistent relationship to protection from subsequent infection.
Antibodies are produced by B cells, and are involved in the maintenance of humoral immunity. Humoral immunity concerns defence against pathogens that operate outside the cells of the body, such as bacteria. Antibodies are not involved in the cell-mediated immunity that operates against pathogens like viruses that
invade cells (see Chapter 2). So serum antibody levels are inadequate as a measurement of the efficacy of vaccines that target viral pathogens such as polio and measles.
The serum concentration of antibodies may give some indication of the level of activation of B cells, and this may be related to the generation of memory B cells, but not necessarily so (see Chapter 6 for a detailed discussion on the problems of defining and evaluating immunological memory). Measuring antibodies leaves the whole area of T cell operation and cell-mediated immunity unaccounted for, along with the operation of antigen presenting cells, and antigen persistence. These were significant areas defined in Ada’s (1994) requirements for the effective operation of a vaccine.
The measurement of serum antibody level has further limitations, in that it is primarily IgG that is measured, although several other types of immunoglobulin molecules, such as IgM, IgA and IgE, are also produced and play important roles at different stages of the immune response (see Sections 2.5, 7.4 and 7.5). There would seem to be a presumption behind this, that IgG is more important than other types of immunoglobulin because it is present in larger amounts. There is,
however, “no firm correlation between these [IgG antibodies] and protection against clinical disease” (Heron 1994, p 389, see also Sections 2.92, 2.95 & 3.8).
Robbins, Schneerson & Szu make the counterclaim that “a critical level of serum IgG antibodies alone can prevent infectious diseases” (1995, p 1389), however they primarily base this assertion on the circular argument that
. . . the only immune response required by FDA and other regulatory agencies for standardization of newly manufactured lots of vaccines is their ability to stimulate protective levels of serum antibodies. (p 1389)
They propose that the technical reason for this is
. . . that licensed vaccines confer protective immunity by eliciting serum IgG antibodies that eliminate the inoculum by killing bacteria, “inactivating” viruses, or neutralizing toxins . . . on mucosal surfaces. (p 1387)
However, inconsistencies in results between similar trials (Clemens, Chuong & Feinstein 1983; Odelram et al 1993), and unexpected vaccine failures support the emphasis placed by Ada (1994a) on the involvement of other elements of the immune system such as other antibody classes and the involvement of cell- mediated as well as humoral immunity (Agbarakwe et al 1994; Donikian, McKee & Greene 1977; Sesardic & Mire-Sluis 2000). So does the fact that protection
afforded by natural infection and live vaccines is greater than that induced by killed vaccines (Donikian, McKee & Greene 1977). All of this indicates that the standard physiological measurement of vaccine efficacy in terms of IgG concentration levels is inadequate.
8.3.1 PERTUSSIS VACCINE
This problem has been discussed with particular reference to pertussis vaccine because of the contradictory findings that:
The two different whole-cell pertussis vaccines most commonly used in the U.S.A. have shown different immunogenicity profiles, but their use has been associated with control of pertussis without clear differences in respective efficacies. (Fritzell 1995, p 86)
whilst
. . . vaccines that appear to have similar immunogenicity may show large differences in clinical efficacy. (Granoff 1999, p 87)
Researchers admit to uncertainty regarding which correlates to measure to determine vaccine efficacy and protection for the recipient:
For pertussis protective immunity there is as yet no serological correlate. (Heron 1994, p 390)
. . . the mechanism by which acellular pertussis vaccines confer protection is poorly understood. (Granoff 1999, p 87)
Some manufacturers have attempted to equate the potency of acellular pertussis vaccines with antigenicity as measured by immunoassay for overall antibody production. There is as yet no objective evidence to equate such responses with clinical efficacy. Indeed such evidence as there is, suggests that there is no correlation. (Corbel 1994, p 357)
The mechanisms of protective immunity against Bordetella pertussis infection following natural exposure or vaccination are still unclear.
Immunogenicity studies during efficacy trials of pertussis vaccines in infants suggested that antibodies are not the sole determinants of resistance to this pathogen. Consequently, cell-mediated immunity (CMI) has been
addressed . . . These studies suggest that CMI is probably an important host determinant of anti-pertussis resistance.
(
Ausiello et al 1998, p 466)Although the need to evaluate cell-mediated as well as humoral immunity to pertussis is now well recognised, the issue has still not been formally addressed in vaccine evaluation regulations (Sesardic & Mire-Sluis 2000). The recognition of the involvement of cell-mediated immunity in resistance to pertussis is particularly interesting as pertussis is a bacterial infection. Current theory holds that only humoral immunity is involved in the defense against extracellular pathogens. The involvement of aspects of cell-mediated immunity indicates that immune responses to pathogens are more complex than previously believed.
8.3.2 Hib VACCINE
With Hib vaccine it is still the case that “the correlates of protection are not known” (Åhman et al 1999, p 2731), and:
It is at present very difficult to estimate what the characteristics are of an immune response that is sufficient for protection after vaccination with Hib conjugate vaccines. (Käyhty 1994, p 400)
However, there is some evidence that anti-Hib antibody does correlate with “protection from invasive infections in humans” (Käyhty 1994, p 397). However, there is little agreement on suitable protective levels. Suggestions for protective levels range from 0.03μg/ml serum (below the limit that can be detected by the commonly used radioimmunoassay test) to 1μg/ml after vaccination, with
considerable variations for individual and ethnic differences. The measurements here refer to anti-Hib polysaccharide antibodies (Käyhty 1994).
Polysaccharides are components of the cell surface, so the antibodies form in response to particular parts of the pathogen, not the pathogen as a whole. This is particularly important with young children, as their immune response to
polysaccharides is limited (Vella & Ellis 1992). It is acknowledged that antibodies to Hib components other than polysaccharides can also contribute to protection (Käyhty 1994), although, as with pertussis, the immune response is more complex than current measurements and regulations are able to address.
. . . it is likely that an elaborate interplay of many antibodies and cell types is necessary for an effectively balanced immune response capable of
preventing invasive Hib infection. (Vella & Ellis 1992, p 15)
A considerable amount of research would be needed to clarify the situation, and this is considered unlikely to happen, because:
Now that Hib conjugate vaccines have become available for infants . . . it is unlikely that additional efficacy studies will be initiated, [so] the protective level of anti-PRP [polyribosyl ribitol phosphate] following vaccination of infants with Hib conjugate vaccines will probably remain unknown. (Vella & Ellis 1992, p 19)
8.3.3 ANTIBODY LEVELS
There is a trend for studies to focus on being able to report that a vaccine
There is an unfortunate, but understandable, proclivity of immunologists to report the protective efficacy of their experimental vaccines at about ten days after the third booster shot, when it is maximal. However, . . . [as] exposure can occur from early age to any time in life thereafter, it is essential that vaccines prime a long term immunologic memory. (Bloom & Widdus 1998, p 483)
Although the stimulation of high levels of antibody production may give the impression that the vaccine is very effective, this is not necessarily the case (see Chapter 4 on Neonatal Tolerance). It has been shown that if a vaccine stimulates a high level of response there tends to be a more rapid decay of antibodies, which is not conducive to the development or maintenance of long-term immunity (Odelram et al 1994).
It has been reported that some vaccines demonstrate greater efficacy if exposure to wild pathogen occurs more than 70 days after immunisation than if exposure occurs within 17 days after immunisation, although circulating antibody levels are usually higher at 17 days than at 70 (Wassilak 1998). Different components of the immune system come in to play at different times after the initial infection or
immunisation. For example, T-helper cell activity can be detected two to three days after infection and some memory T-cells can be detected after 14 days, whilst memory B-cells and antibody secreting cells reach a peak about three months after infection and can still be detected nearly two years later (Ada 1994b). This
suggests that a more realistic evaluation of vaccine efficacy would be obtained from a range of immunological tests performed some months after immunisation, rather than from a simple reading of antibody levels obtained after a few weeks.