ReviewWanted, dead or alive: New viral vaccines
Introduction
The remarkable success of vaccination against a wide spectrum of human pathogens represents one of the great achievements in medicine. In this regard, there is no doubt that live vaccines have played a critical role in controlling many human diseases. The world's first vaccine was developed against smallpox by Edward Jenner (Jenner, 1798, Jenner, 1799, Jenner, 1800) and this breakthrough eventually led to the eradication of natural smallpox (Fenner et al., 1988). Live vaccines have been important in controlling other pathogens including polio (Sabin vaccine, introduced in 1961) and yellow fever virus (introduced in 1936). However, these important advances have not come without a price; smallpox vaccination of the general public resulted in 1–8 deaths per million vaccinations between the 1940s through the 1980s (Kretzschmar et al., 2006). Routine vaccination of civilians was therefore discontinued worldwide in 1980 when the World Health Organization confirmed the global eradication of smallpox. Likewise, routine vaccination with the live oral polio vaccine (OPV) resulted in an average of 9 cases of vaccine-associated paralytic poliomyelitis (VAPP) each year from 1961 to 1989 in the US (Alexander et al., 2004). More recently, OPV vaccination campaigns in Nigeria have also resulted in at least 69 cases of VAPP (CDC, 2007). With these safety concerns, the US replaced the live polio vaccine entirely with the inactivated polio vaccine (IPV) in 2000 and this has led to the complete elimination of VAPP (Alexander et al., 2004). The current yellow fever vaccines (yellow fever 17D or 17DD strains) result in 1–2 deaths per million doses administered (Kitchener, 2004, Lindsey et al., 2008, Struchiner et al., 2004) including fatalities among young, otherwise healthy adults (Doblas et al., 2006, Gerasimon and Lowry, 2005, Vasconcelos et al., 2001). Although the yellow fever vaccine has been described as one of the safest vaccines ever developed, it has been contraindicated in infants since the 1960s due to high rates of encephalitis (Monath, 2004, Sencer et al., 1966) and viscerotropic disease (with ∼50% mortality) occurs in the elderly at an alarming rate of 1 per 50,000 doses (Barrett et al., 2007, CDC, 2005b, Lindsey et al., 2008).
Safety concerns explain why some live attenuated vaccines are eventually replaced by non-replicating or inactivated vaccines (Fig. 1). In general, this represents an evolutionary process; prior to the development of a specific vaccine, people developed immunity by natural infection with wild-type circulating pathogens. In some cases, the infection and disease outcome could be modified by the route of exposure or the age of exposure. Prior to the development of the smallpox vaccine by Edward Jenner, a type of immunization described as “variolation” was practiced. This procedure involved inoculation of a patient's skin with smallpox (variola virus), which resulted in only 0.5–1% mortality in comparison with the natural route of exposure via the respiratory route, which resulted in approximately 30% mortality. Age at the time of infection can play a substantial role in disease outcome. Prior to licensure of the current varicella zoster virus (VZV, i.e., chickenpox) vaccine, it was not uncommon for parents to expose their young children to other VZV-infected children on purpose in order for them to be infected with the virus at a younger age when the disease severity is much less than what is typically observed during primary VZV infection as an older adolescent or as an adult. Induction of immunity through natural infection is often first replaced by vaccine-mediated immunity derived from live, attenuated vaccines. This approach, in turn, may later be replaced by the use of an inactivated or subunit vaccine—especially if there are common (or even rare) severe adverse events (AEs) associated with the original live vaccine. This process may be dictated to a large degree by the spread and severity of the disease itself and the means used to treat it. When smallpox was endemic, the one in a million chance of vaccine-associated death was small compared to the 30% mortality of the disease itself. However, once smallpox was eradicated, the risk:benefit ratio changed sharply. The rare but sometimes severe AEs associated with smallpox vaccination overshadowed its protective use in the absence of an outbreak situation and this resulted in the interest to develop a second generation tissue culture-based vaccine as well as a third-generation non-replicating vaccine based on Modified Vaccinia Ankara (MVA). Likewise, once polio was no longer endemic in the US, the risk of live virus vaccination became higher than the risk of the disease itself—resulting in the shift from using the live attenuated oral Sabin vaccine to the injected Salk vaccine comprised of inactivated virus. The evolution from natural infection to live attenuated vaccines to inactivated vaccines is by no means a universal process. In some cases, such as the Hepatitis B vaccine, the safety and efficacy of the subunit vaccine allowed its routine use without a live attenuated intermediate vaccine being pursued. In contrast, the remarkably high safety profile of the live attenuated measles–mumps–rubella (MMR) vaccine (Amanna and Slifka, 2005) indicates that it is unlikely to be replaced by an inactivated vaccine formulation any time soon.
There remains considerable controversy over the efficacy and use of live vaccines versus inactivated or subunit vaccines. One concern is whether inactivated vaccines can stimulate protective mucosal immunity. A study of 527 infants given the oral polio vaccine (OPV) or IPV followed by OPV demonstrated that partial mucosal immunity was observed after vaccination with IPV (Laassri et al., 2005). Following IPV immunization, there was a 35–56% reduction in the number of infants who shed virus (depending on the serotype) following infection with OPV. Of the IPV-immunized infants who shed virus, the fecal titers were much lower (reduced by 75%). One caveat to this study however, is that two doses of IPV may not have provided the full immunity that is observed after the standard 3-dose schedule. Although IPV may not be as effective as prior OPV immunization in preventing/reducing fecal virus shedding, it is administered by either the intramuscular or subcutaneous routes and is therefore not expected to induce substantial levels of mucosal immunity. However, because IPV blocks systemic spread of the virus in the infected host, it is still 96% effective at protecting against paralytic poliomyelitis (Melnick et al., 1961). An alternative model for examining mucosal responses is presented by cholera vaccines. The most widely used vaccine is Dukoral®, an inactivated orally administered formulation shown to be effective at preventing severe diarrhea in large field trials in Bangladesh (Clemens et al., 1986, Clemens et al., 1990). In contrast, a live attenuated oral cholera vaccine (Orochol®) showed no significant protection in a large field trial in Indonesia (Richie et al., 2000). Together, these results demonstrate that inactivated vaccines can elicit at least some degree of mucosal immunity and provide protection against mucosal pathogens. Moreover, the comparison between inactivated polio and inactivated cholera vaccines suggest that the route of vaccination (intramuscular vs. oral route, respectively) may also play a role in inducing protective immunity at mucosal sites.
Although most current vaccines induce antibody-dependent immunity (Plotkin, 2008, Siegrist, 2008), many vaccinologists still believe that a live virus vaccine is needed to induce strong T cell responses and that strong T cell responses are required for protective immunity. This assumption may be based on historical studies involving human genetic disorders, often described as, “Experiments of Nature” in which affected individuals with deficiencies in either T cell or B cell immunity were studied in terms of their susceptibility to viral and bacterial diseases. In addition, early failures of inactivated vaccines appear to have provided further proof of the superiority of live vaccines over inactivated vaccines but there were often caveats to these early studies that may change their modern interpretation. In the following sections, we will describe some recent changes to our understanding of the mechanisms of vaccine-mediated immunity, compare and contrast live attenuated vaccines versus inactivated vaccines and discuss the future development of new antiviral vaccines.
Section snippets
Genetic deficiencies in humoral immunity
Patients with genetic immune deficiencies have been described as, “Experiments of Nature” since they provide substantial insight into the relative roles of humoral and cell-mediated immunity against infectious disease. In 1952, Bruton published the first case of agammaglobulinemia, in which he described an 8-year-old patient who completely lacked the gamma globulin fraction in serum (i.e., antibody deficient) (Bruton, 1952). This young patient presented with persistent bacterial infections,
Smallpox
There is continuing debate over the relative merits of using live vaccines versus inactivated vaccines (Meldrum, 1999). One of the main concerns is whether an inactivated vaccine can achieve the protective efficacy and duration of immunity that is afforded by a live attenuated vaccine. Some of this concern stems from initial failed or suboptimal attempts to develop inactivated versions of successful live vaccines, such as the smallpox vaccine. In order to decrease the risk associated with live
Role of antibody and T cells during primary infection versus secondary infection
Genetic or antibody-mediated depletion of T cells during primary infection has demonstrated how important T cells are for the induction of antiviral immunity in many animal models. However, similar to the “Experiments of Nature” in which human patients lack T cell function due to genetic deficiencies, it is important to note that effective antibody responses can be directly affected by T cell deficiency. For instance, if a mouse lacks the ability to mount an antibody response, then antiviral T
Both live and inactivated vaccines require boosters
It is generally accepted that inactivated vaccines require at least one or two booster vaccinations in order to elicit optimal long-term protective immunity. However, one central dogma of vaccinology is that live vaccines are superior to non-replicating vaccines because with live attenuated vaccine viruses, “one shot induces lifelong immunity”. Although this is indeed the case for many natural viral infections, it not the case following immunization with many live attenuated vaccines (Table 1).
Conclusions
Re-examination of “Experiments of Nature” involving patients with genetic immunodeficiencies has shed new light on the role of antibody and T cells in protecting against viral infections. Although there are cases in which T cell responses are able to compensate for the lack of humoral immunity, many patients with agammaglobulinemia remain highly susceptible to a wide range of viral infections. Clinical outcome has been improved by repeated administration of high-dose gamma globulin and this has
Acknowledgements
This work was supported by NIH grants, R43 AI079898 (I.J.A., M.K.S.) R56 AI076506 (M.K.S.), U54 AI081680 (co-investigator, M.K.S.), UO1 AI082196 (M.K.S.) and Oregon National Primate Research Center grant, RR000163 (M.K.S.).
OHSU, Dr. Slifka, and Dr. Amanna have a financial interest in Najít Technologies, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by OHSU and the Integrity
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