The immunology of smallpox vaccines

Abstract

In spite of the eradication of smallpox over 30 years ago; orthopox viruses such as smallpox and monkeypox remain serious public health threats both through the possibility of bioterrorism and the intentional release of smallpox and through natural outbreaks of emerging infectious diseases such as monkeypox. The eradication effort was largely made possible by the availability of an effective vaccine based on the immunologically cross-protective vaccinia virus. Although the concept of vaccination dates back to the late 1800s with Edward Jenner, it is only in the past decade that modern immunologic tools have been applied toward deciphering poxvirus immunity. Smallpox vaccines containing vaccinia virus elicit strong humoral and cellular immune responses that confer cross-protective immunity against variola virus for decades after immunization. Recent studies have focused on: establishing the longevity of poxvirus-specific immunity, defining key immune epitopes targeted by T and B cells, developing subunit-based vaccines, and developing genotypic and phenotypic immune response profiles that predict either vaccine response or adverse events following immunization.

Figure 1

Immune response pathways activated by smallpox vaccines. Immunization with the smallpox vaccines elicits a cascading network of integrated immune pathways. Non-specific innate responses activated by pattern recognition receptors serve to inhibit initial viral replication and to activate antigen presenting cells in order to properly initiate adaptive immunity. Innate inflammatory cytokines and chemokines then attract effector lymphocytes into infected tissues. T helper cells supply necessary cytokines (IL-4, IL-5) and costimulatory signals (CD40L) for the B cell maturation, replication and isotype switching. T cell help (IL-2, IFNg) also promotes CTL activation, clonal expansion and effector function. VACV-specific T helper cells can also have direct lytic activity. B cells produce antibodies that agglutinate, opsonize, and neutralize viral particles, fix complement and allow for antibody dependent cell cytotoxicity (ADCC). Activated CD8 T cells lyse infected cells through perforin, granzymes, and through death receptors such as FasL. Cytokine secretion (IFNg, TNFa) by T lymphocytes can also have direct antiviral activity. Together humoral and adaptive responses halt viral replication, lyse infected cells, and remove viral particles from the host. Virus-specific lymphocyte numbers then contract to a small, long-lived memory population capable of rapidly responding to subsequent infection with VACV and more. Electron micrograph of vaccinia virus adapted from the Centers for Disease Control and Prevention Public Health Image Library, image #2143.