The published record about vaccines is "scattered and confusing" on several critical issues, says Stanley A. Plotkin of the University of Pennsylvania in Philadelphia.
His minireview, which cuts through some of that confusion, is published in the July 2010 Clinical and Vaccine Immunology (17:1055-1065).
One particularly important issue that Plotkin raises deals with longconfusing semantics, says Polly Matzinger of the National Institutes of Health in Bethesda, Md. In discussing vaccines, investigators often refer to "correlates" and "surrogates" of protection interchangeably. However, the two terms describe distinct phenomena, and Plotkin carefully redefines them, clearing up that lingering ambiguity. Thus, he describes correlates of vaccine- induced immunity as those immune functions that are responsible for protection. Meanwhile, surrogates of protection are immune responses that can be measured as stand-ins for protection but which are not themselves protective. "For most [licensed vaccines], there is a functional antibody that correlates with protection, but for a few, a surrogate measurement is used to infer protection," he says.
Correlates are useful when they help to predict whether a vaccine will protect against a particular infectious disease and it is not feasible to determine that fact directly. They also can be used to measure susceptibility of an individual or population to a disease for which a protective vaccine is available, he says.
When trying to assess efficacy of a particular vaccine, clinical researchers prefer a single, measurable mechanism, according to Plotkin. Although he identifies many of them, in reality, immune responses to vaccines are multiple and redundant, he emphasizes. Even so, not all antibodies that an individual produces in response to a vaccine are functional. "People produce a variety of antibody types when they are exposed to an agent," he says. "Some are functional; some aren't."
Plotkin says further that "almost all of the vaccines we have now work through antibodies, either in the blood or on the mucosa." Many infections go through a phase where the pathogens responsible for them are carried in the blood and thus antibodies can neutralize them.
In his review, Plotkin describes correlates of protection among different pathogens. But he also articulates six general principles that serve as foundations for understanding specific examples of protection- or failure. (i) Large challenge doses may overwhelm vaccine-induced immunity, confusing the identification of correlates. (ii) The mechanism of protection is not necessarily the mechanism of recovery from infection. The latter may work through cellular immunity and may be irrelevant to vaccine-induced prevention. (iii) Most current vaccines act through functional antibodies. Nonetheless, because the immune system is redundant, vaccines may work through multiple mechanisms. (iv) Memory induced by vaccination may be critical to protection, particularly in the case of infections, such as those involving the hepatitis B virus, with long incubations. (v) Correlates may vary with the age, gender, and major histocompatibility complex signature of an individual. (vi) Correlates may differ depending on whether prevention targets systemic infection, mucosal infection, disease, or severe disease.
Plotkin also describe situations for nine categories of pathogen, including encapsulated bacteria, toxin-producing bacteria, viruses transmitted by arthropods, hepatitis, and rabies.
"After the administration of nearly all licensed vaccines, with the exceptions of BCG and zoster, prevention of infection correlates with the induction of specific antibodies," Plotkin notes. "Antibodies must be present at the site of replication on the mucosae or in specific organs and must have sufficient breadth to affect heterologous serotypes, if they exist."
Furthermore, CD4+ responses that are key to helping B cells, which make antibodies, and to producing cytokines sometimes correlate better with protection than do antibody titers. "Antibodies prevent infection, whereas cellular responses control infection once replication has been established," Plotkin concludes. "It is likely that vaccines of the future, such as those for HIV, will obey the same paradigm."
David C. Holzman
David C. Holzman is the Microbe Journal Highlights Editor.
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