The idea of immunization originated to combat smallpox with the practice of "variolation"- inoculation with scabs from individuals who had suffered mild disease. In the 1790's, Edward Jenner introduced the practice of inoculation with cowpox, a relative of smallpox that didn't cause significant disease in humans but induced protective immunity.
Subsequent development of vaccines progressed with Pasteur's rabies vaccine in the late 1800's and the development of a host of vaccines in the 1900's.
There are two classic types of viral vaccines- "live attenuated" and "killed" or "fixed".
>Live, attenuated vaccines are either nonpathogenic relatives of the target virus (like Jenner's cowpox) or are produced by "attenuation" of virulent isolates by passage in animals and/or cell culture.
>Fixed vaccines consist of purified virus which has been activated by UV light or chemical treatment that destroys infectivity without affecting antigenicity.
There are advantages and disadvantages to each type of vaccine:
Live, attenuated vaccines:
>Advantages:
Because of attenuation, vaccination mimics a subclinical infection resulting in induction of a complete immune response, including IgG and IgA antibodies, CD4+ and CD8+ T lymphocytes and memory cells.
Dosage administered is small leading to low cost of preparation and limited allergic response
Theoretically, only one dose is necessary, although often more doses are recommended
>Disadvantages:
Since the virus is a live agent, virulent replication or reversion to virulence can occur
Live vaccines are labile
Interference with natural agents can occur leading to vaccine failure
Fixed vaccines:
>Advantages:
No side effects are encountered due to viral replication
It is easier to predict the response to inoculation
Fixed vaccines are stable
>Disadvantages:
The immune response induced is similar to that induced against an antigen and thus only IgG is induced, the cell mediated immune response induced is uncertain, and serum immunity wanes and boosters are required for maintenance
Adjuvent can be required to maximize the immune response
Fixed vaccines require large amounts of pure antigen
Both live and fixed vaccines are currently in use:
Poliovirus:
Both fixed (Inactivated Polio Vaccine, IPV, developed by Jonas Salk) and live, attenuated (Oral Polio Vaccine, OPV, developed by Albert Sabin) polio vaccines have been used. Both are trivalent, containing all three poliovirus serotypes. Initially IPV was given, but ~1960 OPV became the standard vaccine and is the vaccine in use in worldwide eradication efforts. In the U.S., three doses of OPV were given to infants because of possible interference due to concurrent inapparent enterovirus infection at the time of vaccination. Unfortunately, the OPV (particularly the Serotype 3 component) reverts to neurovirulence, causing a few (<10) cases of poliomyelitis per year. Thus recently, the vaccine regimen was changed to two doses of IPV followed by a dose of OPV.
Measles, Mumps, Rubella:
Live, attenuated vaccines for all three viruses were developed in the 1960's. In the U.S., these vaccines are administered by intramuscular injection in trivalent form. The three viruses do not interfere with each other. Initially, only one dose was given at 15-18 months of age, however after the 1989-1991 resurgence of measles, a second dose was added at 5-10 years of age to insure complete coverage.
Varicella:
The Varicella live, attenuated vaccine was developed in the 1960's but was only licensed for use recently. Currently, it is recommended, but not required.
Smallpox:
Interestingly, the virus that was eventually mass-produced as a smallpox vaccine turned out to be a unique virus that is a recombinant between smallpox virus and the cowpox virus used by Jenner. This virus, vaccinia virus, was used in the smallpox eradication efforts. Being a live virus, there are vaccinia-associated complications which include encephalitis, however these were acceptable considering the nature of smallpox itself. Smallpox was certified eradicated in 1988 by the WHO and all smallpox vaccination was terminated. Smallpox virus still exists in freezers at the CDC in the U.S. and in Moscow and supplies of smallpox vaccine have dwindled. With the renewed threat of using agents like smallpox for bioterrorism, it is considered necessary to have smallpox vaccine stockpiled for use in case of a bioterroristic release of the agent. However, considering the complications associated with vaccinia virus, development of a new smallpox vaccine has been mandated.
Hepatitis A:
Development of a hepatitis A vaccine was hindered by the initial inability to grow the virus in cell culture. However, that problem was overcome and a vaccine consisting of inactivated virus is now available and recommended for individuals traveling in areas in which hepatitis A is endemic.
Hepatitis B:
The hepatitis B vaccine is actually a subunit vaccine (which is similar in usage to a fixed vaccine) composed of surface antigen or HbsAg. The initial vaccine consisted of HbsAg prepared from donors' serum, but now is manufactured in yeast. The vaccine was originally recommended for individuals in at-risk populations, but now is a required universal vaccine given to infants (3 doses).
New vaccine approaches:
Live vaccine approaches:
>Engineered viruses- viruses which have been mutagenized in a directed manner to reduce virulence and prevent reversion
>Genetic reassortants- this approach is used with segmented viruses. Different parental viruses are used to co-infect cells and reassortants with desired properties are selected. For example:
-Temperature sensitive mutants of influenza virus have been isolated and found to exhibit decreased virulence because their replication in humans is restricted due to the temperature sensitivity; nevertheless an immune response is induced. Reassortants between ts- viruses and currently circulating strains are selected which maintain the ts- phenotype and have the HA and NA proteins from the current strains. These vaccines are admininstered intranasally as a mist.
-The rotavirus vaccine that was recently licensed is a reassortant between an avirulent rhesus monkey rotavirus and human rotaviruses. The vaccine is tetravalent: one component is the rhesus monkey virus which has the antigenicity of the human G3 serotype, the other components contain all of the monkey virus gene segments except that encoding the VP7 gene product, which comes from the human G1, G2, and G4 viruses, respectively. This vaccine was administered orally. Unfortunately, with its licensed usage, the vaccine has been associated with intussusception (blockage of the small intestine) and therefore the vaccine has been suspended.
>Live vaccine vectors- Vaccinia virus, a large DNA virus, has been engineered to express the immunogenic proteins of a number of viruses. However, given that a substantial percentage of the world's population is immune to Vaccinia due to smallpox vaccination and adverse effects associated with the vaccine, current vectoring has switched to avian poxviruses including canarypox virus.
Fixed vaccine approaches:
>Subunit vaccines produced by recombinant DNA technology- such as the Hepatitis B virus vaccine and the gp160 component of the HIV vaccine candidate. Although the usual vectors for production of these subunits are bacteria, yeast, and insect cells infected with baculoviruses expressing the subunits, plants (such as potatoes) have been engineered to produce such subunits which would result in induction of an immune response by simply eating the bioengineered product
>Peptide vaccines- a cocktail of peptides from virus proteins known to be recognized by neutralizing antibodies and the MHC class I and II complexes
>DNA vaccines- DNA plasmids that express immunogenic virus proteins have been found to do so when injected into animals, resulting in induction of an immune response.
HIV Vaccines:
The pattern of HIV transmission, at least in the U.S., has changed due to eliminating transmission through the blood supply and through education and awareness programs that have changed (to some extent) sexual practices that enhanced transmission. Additionally, antiviral therapies are available that thus far offer long term survival provided that the antiviral regimen is followed. Yet antiviral therapy is prohibitively expensive and HIV is at pandemic levels in many regions of the world. Therefore, to combat HIV on a worldwide basis, an effective vaccine is needed.
There are a number of problems with development of an HIV vaccine:
1. The virus is uniformly fatal despite an immune response induced against it. Therefore, it is not clear what constitutes "effective immunity" that a vaccine should stimulate. It is therefore thought that infection should be stopped at the point of viral entry, ie genital secretions, and therefore induction of a secretory response (both humoral and cellular) appears to be essential. HIV infection may be primarily in the form of infected cells and a secretory cellular response would definitely be necessary to stop this form of infection.
2. The virus is highly mutable, with at least seven genotypic clades worldwide. Additionally, antibodies induced against lab-adapted strains of HIV (that are used to prepare vaccines) do not neutralize naturally occurring "field" strains of HIV.
3. Testing in humans is difficult because vaccine recipients cannot be challenged with the virus, but must acquire it naturally (and must be counseled not to do so).
4. There is no animal model.
The first generation of HIV vaccines were bioengineered gp160 subunits which were found to be nontoxic (Phase I trials). Phase II trials (double blind testing on a limited number of participants) progressed, however at the time of expanded Phase III trials, it was found that some of the Phase I and II participants who received the vaccine had been infected with HIV. This led to suspension of the Phase III trials (large scale double-blind testing). There then followed a lull in HIV vaccine development. Recently, HIV vaccine efforts have been centralized at NIH and human testing has been reinitiated. Vaccines currently being tested consist of initial inoculations with recombinant canarypox vectors expressing up to 4 of the viral genes followed by inoculation with gp160 subunit vaccine.
Vaccination Strategy and Policy
With the availability of vaccines, the strategy for their use depends on the disease and need for prevention of it. Generally speaking, there are two approaches: "Universal coverage" and "At-risk group targeting" as have been discussed for specific vaccines above.
Viral Eradication through Vaccination:
Not all viral disease are eradicable. The necessary features for eradication are:
Smallpox fit all of these criteria and was eradicated in 1977. The next two diseases considered were polio and measles, which do not fit all of these criteria. However, in 1988 the WHO endorsed a worldwide eradication of polio program to be completed by 2000. Polio was eliminated from the Western Hemisphere in 1991; by 1997 the world case rate of paralytic polio was a few thousand cases per year (a 99% decrease). Currently, polio remains endemic only in Central Africa and Southeast Asia. The final elimination effort relies on: worldwide implementation of routine vaccination schedules, maintenance of a worldwide surveillance system with regional offices; National Immunization Days; and mop up vaccination efforts in areas with instability, refugees, or high rates of migration. It is hoped that the infrastructure developed in the polio eradication effort will then provide the basis for measles elimination.