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Many of the images in the smallpox part of this file come from Fenner, Henderson, Arita et al. Smallpox and its Eradication. 1988 Geneva, World Health Organization and were assembled by Laura Gregorio in her essay The Smallpox Legacy, Pharos. Fall 1996 |
INTRODUCTION What is a vaccine? Vaccines are harmless agents, perceived as enemies. They are molecules, usually but not necessarily proteins, that elicit an immune response, thereby providing protective immunity against a potential pathogen. While the pathogen can be a bacterium or even a eukaryotic protozoan, most successful vaccines have been raised against viruses and here we shall deal with anti-viral vaccines. Immunity to a virus normally depends on the development of an immune response to antigens on the surface of a virally infected cell or on the surface of the virus particle itself. Immune responses to internal antigens often play little role in immunity. Thus, in influenza pandemics, a novel surface glycoprotein acquired as a result of antigenic shift characterizes the new virus strain against which the population has little or no immunity. This new strain of influenza virus may, nevertheless, contain internal proteins that have been in previous influenza strains. Surface glycoproteins are often referred to as protective antigens. To make a successful vaccine against a virus, the nature of these surface antigens must be known unless the empirical approach of yesteryear is to be followed. It should be noted, however, that a virally-infected cell displays fragments of internal virus antigens on its surface and these can elicit a cytotoxic T cell response that acts against the infected cell. There may be more than one surface glycoprotein on a virus and one of these may be more important in the protective immune response than the others; this antigen must be identified for a logical vaccine that blocks infectivity. For example, influenza virus has a neuraminidase and a hemagglutinin on the surface of the virus particle. It is the hemagglutinin that provokes neutralizing immunity because it is the protein that attaches the virus to a cell surface receptor and the neutralizing antibody interferes with virus binding to the cell. In addition to blocking cell to virus attachment, other factors can be important in the neutralization of viruses; for example, complement can lyse enveloped virions after opsonization by anti-viral antibodies.
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Major sites of viral infection In order to develop a successful vaccine, certain characteristics of the viral infection must be known. One of these is the site at which the virus enters the body. Three major sites may be defined:
IgA-mediated local immunity is very important in types 1 and 2. There is little point in having a good neutralizing humoral antibody in the circulation when the virus replicates, for example, in the upper respiratory tract. Clearly, here secreted antibodies are important. Thus, we need to know:
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Figure 1 Comparison of maximum and current morbidity for vaccine-preventable
diseases |
Types of vaccines There are four basic types of vaccine in use today
Problems in vaccine development There are many problems inherent in developing a good protective anti-viral vaccine. Among these are:
Despite these problems, anti-viral vaccines have, in some cases, been spectacularly successful (figure 1) leading in one case (smallpox) to the elimination of the disease from the human population. The smallpox vaccine is an example of an attenuated vaccine, although not of the original pathogenic smallpox virus. Another successful vaccine is the polio vaccine which may lead to the elimination of this disease from the human population soon. This vaccine comes in two forms. The Salk vaccine is a killed vaccine, while that developed by Albert Sabin is a live attenuated vaccine. Polio is presently restricted to parts of Africa (Nigeria and surrounding countries and south Asia (India, Pakistan and Afghanistan).
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Figure 1aMary Wortley Montague The work of art depicted in this image and the reproduction thereof are in the public domain worldwide. The reproduction is part of a collection of reproductions compiled by The Yorck Project. The compilation copyright is held by Zenodot Verlagsgesellschaft mbH and licensed under the GNU Free Documentation License. |
PAST SUCCESSES SMALLPOX (Variola) Smallpox is a devastating and disfiguring disease that is highly infectious. It is caused by variola virus (also known as smallpox virus), a member of the orthopoxvirdae (figure 2A). The disease of smallpox has been known for thousands of years and probably originated in Asia. It spread westwards into the middle east and among its victims was Pharaoh Rameses V (figure 2B). The disease may have reached Europe with the crusaders. Smallpox was introduced to the New World by European colonists and caused devastating epidemics in the indigenous population who had no natural immunity. Indeed, some early colonists used smallpox as a biological weapon again the original inhabitants of North and South America. Smallpox is characterized by numerous pustules containing infectious virus all over the body (figure 2 C and D). The fatality rate is more than one quarter of infected patients infected by the most serious form caused by Variola major. Another form of smallpox caused by Variola minor has a much lower fatality rate (up to 5%). The first attempts to control smallpox occurred in the 10th century and used variolation (so called because small pox virus is Variola). In variolation (figure 2E), material (scabs) was obtained from the pustules of an infected person who did not die of the disease. This person, therefore, had a milder form of smallpox as a result of a naturally occurring variant. This material was used to infect another person who usually also got a milder disease. If the person did not die, there was lifelong immunity. Another reason for the success of variolation is that virus in the scabs was less virulent because it had been partially desiccated and was complexed with and inactivated by antibodies from the donor. The fatality rate of variolation is about 1 - 2% and so it was still a dangerous procedure. This technique was used in Pakistan, Ethiopia and Afghanistan until 1970. Variolation was widespread in England in 1700s where it was introduced by the wife of the British Ambassador to Turkey, Mary Wortley Montague (figure 1a).
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2
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B.
The mummified head of
Ramses V (died 1157 BCE)
with rash that
is probably the result
of smallpox |
C.
Infant with smallpox |
E. Powdered smallpox scabs were inhaled to
protect against smallpox in Chinese medicine |
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D. Smallpox lesions on skin of trunk. Photo taken in Bangladesh.
CDC/James Hicks |
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Figure 3
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 B. Dr Jenner about to vaccinate a child |
 C. Blossom the
cow |
F. The last known person in the world to have a natural case of smallpox. Variola minor in 23-year-old Ali Maow
Maalin, Merka, SomaliaCDC |
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Jenner was a physician living in rural Gloucestershire in the west of England and it was widely known at that time that people who contracted cowpox (such as dairy maids) appeared to gain protective immunity against the much more virulent smallpox. Jenner vaccinated a Mr Phipps (who worked for him) and own son (figure 3B) with cowpox from a cow called Blossom (figure 3C), and then challenged them with virulent smallpox. Both vaccinees were, fortunately, protected. Jenner's original virus is not the vaccinia that was used in smallpox vaccinations until recently. The vaccine virus may have arisen as recombinant from cowpox or horse pox. For a long time the vaccine virus was maintained in horses or buffalo. The last case of natural smallpox in the U.K. occurred in the 1930s; the last in the U.S.A. was in the 1940s. The last natural case in the world was in Somalia and occurred in October 1977 (figure 3D). Although the virus had been eliminated in the wild, smallpox was retained in the laboratory and as a result of a laboratory accident there was subsequently a fatal case of smallpox in England. Worldwide stocks were reduced to laboratories in the United States and the Soviet Union. It is not known whether infectious virus from the Russian laboratory was distributed after the dissolution of the Soviet Union. The eradication of smallpox has been one of the great triumphs of public health. There are several reasons for this:
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 Figure 4.Louis Pasteur
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RABIES Almost a century after Jenner's pioneering
work on smallpox, in 1885 Louis Pasteur (figure 4) and Emile Roux developed the first
vaccine against rabies (figure 5) (rabhas, Sanskrit: to do violence).
Pasteur discovered that if he took spinal cord material from a dead rabid rabbit
and kept it for a period of 15 days in a dry atmosphere (a flask containing
potassium hydroxide) and then injected it into a dog, the latter did not get
rabies. He developed a protocol in which he carried out the same procedure with
spinal cord tissue that had been kept in a dry atmosphere for less and less time
(each was separated by an interval of two days), until he finally injected
spinal tissue containing virulent virus (only a day or two in the flask). He
found that the dog was then immune to rabies.
Pasteur successfully treated a boy (Joseph Meister) bitten by a rabid dog
sixty hours earlier with this protocol in which he used successively more
virulent virus. In fact, according to Pasteur, the rabies in the final
inoculation was more virulent than that of ordinary canine rabies. Fortunately,
Mr Meister survived both the initial bites and the virulent virus! A recombinant anti-rabies vaccine (VRG, Raboral) has been made by inserting the gene for the surface glycoprotein of rabies into vaccinia virus, the virus used in smallpox vaccinations. The recombined virus appears safe for humans but is used for treating wild animals since (because it is a live virus) it can give herd immunity. The vaccine virus stable to elevated temperatures and can be delivered orally. It is therefore fed to animals in food baits. See also Rabies virus
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Polio - Current
global case count VIDEO
Race to reach
the last child |
In
western countries, wild type polio is no longer a problem but it is still
found in some less developed countries such as Nigeria, Pakistan,
Afghanistan and India (figures 4,
5 and 6). Until the 1950s, when anti-polio vaccination became routine,
summer outbreaks of polio were common in western countries, often spread
via the oral-fecal route while using swimming pools. These outbreaks led
to widespread paralytic polio that necessitated help in breathing and the
use of "iron lungs" (figure 7). See also Picornaviruses
Vaccines There are two types of polio vaccine, both of which were developed in the 1950s. The first, developed by Jonas Salk, is a formalin-killed preparation of normal wild type polio virus. This is grown in monkey kidney cells and the vaccine is given by injection. It elicits good humoral (IgG) immunity and prevents transport of the virus to the neurons where it would otherwise cause paralytic polio. This vaccine is the only one used in some Scandinavian countries where it completely wiped out the disease. A second vaccine was developed by Albert Sabin. This is a live attenuated vaccine that was produced empirically by serial passage of the virus in cell culture. This resulted in the selection of a mutated virus that grew well in culture and, indeed, in the human gut where the wild type virus grows. It cannot, however, migrate to the neurones. It replicates a normal infection since the virus actually grows in the vaccinee and it elicits both humoral and cell-mediated immunity. It is given orally, a route that is taken by the virus in a normal infection since the virus is passed from human to human by the oral-fecal route. This became the preferred vaccine in the United States, United Kingdom and many other countries because of it ease of administration (often on a sugar lump), the fact that the vaccine virus replicates in the gut and only one administration is needed to get good immunity (though repeated administration was usually used). In addition, the immunity that results from the Sabin vaccine lasts much longer that that by the Salk vaccine, making fewer boosters necessary. Since it elicits mucosal immunity (IgA) in the gut, the Sabin vaccine has the potential to wipe out wild type virus whereas the Salk vaccine only stops the wild type virus getting to the neurons. The attenuated Sabin vaccine, however, came with a problem: back mutation. This may result from recombination between wild type virus and the vaccine strain. Virulent virus is frequently isolated from recipients of the Sabin vaccine. The residual cases in countries that use the attenuated live virus vaccine (about 8 per year in the US until recently) resulted from mutation of the vaccine strain to virulence. About half of these cases were in vaccinees and half in contacts of vaccinees. Paralytic polio arises in 1 in 100 cases of infection by wild type virus and 1 in 4 million vaccinations as a result of back reversion of the vaccine to virulence. This was deemed acceptable as the use of the attenuated virus means that the vaccine strain of the virus still replicates in the body and gives gut immunity via IgA. The vaccinee who has received killed Salk vaccine still allows wild type virus to replicate in his/her gastro-intestinal tract, since the major immune response to the injected killed vaccine is circulatory IgG. As noted above, this vaccine is protective against paralytic polio since, although the wild type virus can still replicate in the vaccinee's gut, it cannot move to the nervous system where the symptoms of polio are manifested. Thus, wild type virus is unlikely to die out in populations who have received only the killed vaccine since it would be shed in the feces. It should be noted, however, that studies in The Netherlands during a polio outbreak in 1992 (among people who had refused the vaccine) showed that immunity produced by the Salk vaccine did prevent circulation of wild type virus in the general population. An additional problem of using a live attenuated vaccine is that preparations may contain other pathogens from the cells on which the virus was grown. This was certainly a problem initially because the monkey cells used to produce the polio vaccine were infected with simian virus 40 (SV40) and this was also in the vaccine. SV40 is a polyoma virus and has the potential to cause cancer. It appears, however, not to have caused problems in vaccinees who inadvertently received it. There have been some allegations that the original attenuated polio vaccine used in Africa may have been contaminated with human immunodeficiency virus (HIV). This has been found NOT to be the case. Of course, there can also be similar problems with the killed vaccine if it is improperly inactivated. This has also occurred. Current recommendations concerning polio vaccines Once the only polio cases in the US were vaccine-associated, the previous policy of using the Sabin vaccine only was reevaluated. At first, both vaccines were recommended with the killed vaccine first and then the attenuated vaccine. The killed vaccine would stop the revertants of the live vaccine giving trouble by moving to the nervous system. Thus, in 1997 the following protocol was recommended: To reduce the vaccine associated cases (8 to 10 per year), the CDC Advisory Committee on Immunization Practices (ACIP) has recommended (January 1997) a regimen of two doses of the injectable killed (inactivated: Salk) vaccine followed by two doses of the oral attenuated vaccine on a schedule of 2 months of age (inactivated), 4 months (inactivated), 12-18 months (oral) and 4-6 years (oral). Currently four doses of the oral vaccine are typically administered in the first two years of life. It is thought that the new schedule will eliminate most of the cases of vaccine-associated disease. This regimen has already been adopted by several European countries and some of Canada. The regimen of polio vaccination was subsequently amended again in 2000: To eliminate the risk for Vaccine-Associated Paralytic Poliomyelitis, the ACIP recommended an all-inactivated poliovirus vaccine (IPV) schedule for routine childhood polio vaccination in the United States. As of January 1, 2000, all children should receive four doses of IPV at ages 2 months, 4 months, 6-18 months, and 4-6 years. Go here (Notice to Readers: Recommendations of the Advisory Committee on Immunization Practices: Revised Recommendations for Routine Poliomyelitis Vaccination) Other commonly used anti-viral vaccines are listed in table 1. |
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CASE REPORT Poliovirus Infections in Four Unvaccinated Children --- Minnesota, August--October 2005 |
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Figure 4.Polio -2004 WHO |
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5 - Polio Statistics Comparison of worldwide incidence in 1988 and 1998
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Figure 6ATotal reported cases in Sweden and Finland (1950-76) which use the killed vaccine only developed by Jonas Salk. The Salk vaccine is injected |
Figure 6BReported (cases per 100,000 population) cases of paralytic poliomyelitis in the United States 1951-1992 which initially used the killed Salk vaccine. This was subsequently replaced by the live attenuated oral vaccine developed by Albert Sabin. The Sabin vaccine is swallowed. It is often given on a sugar lump |
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Figure 6CPoliomyelitis in the US 1980-1995 CDC |
Figure 6DOutbreaks in US since 1970 CDC |
Figure 6EVaccine-associated paralytic polio - VAPP CDC |
Figure 6FVaccine-associated paralytic polio - VAPP in US 1964-1995 CDC |
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Figure 6GVaccine-associated paralytic polio 1980-94 |
Figure 6HRisk of vaccine- associated paralytic polio 1980-94 |
Figure 6IRisk of vaccine- associated paralytic polio in recipients 1980-94 |
Figure 6JVaccine-associated paralytic polio - risks in contacts 1980-94 CDC |
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| Figure
7 -
Poliomyelitis
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B. Iron lung ward |
C. Child with polio sequelae WHO |
D. Child with polio sequelae WHO |
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E. Victims of polio WHO |
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VACCINES - GENERAL
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Attenuation is usually achieved by passage of the virus in foreign host such as embryonated eggs or tissue culture cells. From among the many mutant viruses that exist in a population (especially so in RNA viruses), some will be selected that have a better ability to grow in the foreign host (higher virulence). These tend to be less virulent for the original host. To produce the Sabin polio vaccine, attenuation was only achieved with high inocula and rapid passage in primary monkey kidney cells. The virus population became overgrown with a less virulent strain (for humans) that could grow well in non-nervous (kidney) tissue but not in the central nervous system. Non-virulent strains of all three polio types have been produced for the vaccine. Molecular basis of attenuation We do not know the basis of attenuation in most cases since attenuation was achieved empirically. The empirical foreign-cell passage method causes many mutations in a virus and it is difficult to determine which are the important mutations. Many attenuated viruses are temperature-sensitive (that is, they grow better at 32 - 35 degrees than 37 degrees) or cold adapted (they may grow at temperatures as low as 25 degrees). In the type 1 polio virus attenuated vaccine strain, there are 57 nucleotide changes in the genome, resulting in 21 amino acid changes . One third of the mutations are in the VP1 gene (this gene is only 12% of genome). This suggests that attenuation results from changes in surface proteins of the virus Recently, an attenuated nasal vaccine for influenza has been developed (see below). This contains cold-adapted vaccine strains of the influenza virus that have been grown in tissue culture at progressively lower temperatures. After a dozen or more of these passages, the virus grows well only at around 25° and in vivo growth is restricted to the upper respiratory tract. Studies showed that influenza illness occurred in only 7 percent of volunteers who received the intra-nasal influenza vaccine, versus 13 percent injected with trivalent inactivated influenza vaccine and 45 percent of volunteers who were given placebo. Both vaccine comparisons with placebo were statistically significant. |
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Figure 8 Secretory antibody (nasal and gut
IgA) and serum antibody (serum IgG, IgM and IgA) in response to killed polio vaccine (left)
administered by intramuscular injection and to live attenuated polio vaccine
(right) administered orally |
Disadvantages of Attenuated vaccine
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Advantages of inactivated vaccine
Disadvantages of inactivated vaccines
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Figure 9 Attenuated influenza vaccine strain using a cold-sensitive mutant that
can be reassorted with new virulent strains |
New methods of vaccine production Selection for mis-sense The attenuated influenza vaccine, called FluMist, uses a cold-sensitive mutant that can be reassorted with any new virulent influenza strain that appears (figure 9). The reassorted virus will have the genes for the internal proteins from the attenuated virus (and hence will be attenuated) but will display the surface proteins of the new virulent antigenic variant. Because this is based on a live, attenuated virus, the customization of the vaccine to each year's new flu variants is much more rapid than the process of predicting what influenza strains will be important for the coming flu season and combining these in a killed vaccine.
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Synthetic peptides Injected peptides which are much smaller than the original virus protein raise an IgG response but there is a problem with poor antigenicity. This is because the epitope may depend on the conformation of the virus as a whole. A non-viral example that has achieved some limited success is a prototype anti-malarial vaccine. |
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Figure 10 Anti-idiotype antibodies |
Anti-idiotype
vaccines An antigen binding site in an antibody is a reflection of the three-dimensional structure of part of the antigen, that is of a particular epitope. This unique amino acid structure in the antibody is known as the idiotype which can be thought of as a mirror of the epitope in the antigen. Antibodies (anti-ids) can be raised against the idiotype by injecting the antibody into another animal. This gives us an anti-idiotype antibody and this, therefore, mimics part of the three dimensional structure of the antigen, that is, the epitope (figure 10). This can be used as a vaccine. When the anti-idiotype antibody is injected into a vaccinee, antibodies (anti-anti-idiotype antiobodies) are formed that recognize a structure similar to part of the virus and might potentially neutralize the virus. This happens: Anti-ids raised against antibodies to hepatitis B S antigen elicit anti-viral antibodies. |
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Recombinant DNA techniques
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DNA Vaccines The Third Vaccine Revolution These vaccines are based on the deliberate introduction of a DNA plasmid into the vaccinee. The plasmid carries a protein-coding gene that transfects cells in vivo at very low efficiency and expresses an antigen that causes an immune response. These are often called DNA vaccines but would better be called DNA-mediated or DNA-based immunization since it is not the purpose to raise antibodies against the DNA molecules themselves but to get the protein expressed by cells of the vaccinee. Usually, muscle cells do this since the plasmid is given intramuscularly. It should be noted that the plasmid does not replicate in the cells of the vaccinee, only protein is produced. It has also be shown that DNA can be introduced into tissues by bombarding the skin with DNA-coated gold particles. It is possible to introduce DNA into nasal tissue in nose drops. In the case of the gold bombardment method, one nanogram of DNA coated on gold produced an immune response. One microgram of DNA could potentially introduce a thousand different genes into the vaccinee.
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Advantages of DNA vaccines
All of the above means that DNA vaccines are cheap and therefore likely to be developed against pathogens of lesser economic importance (at least to drug companies)
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Possible Problems
Initial studies Most work has been done on DNA vaccines against viruses since DNA-based plasmid immunization actually resembles virus infection. When they have been well-characterized, the immune responses are broad-based and mimic the situation seen in a normal infection by the homologous virus. The immune response can be remarkably long-lasting and even more so after one booster injection of plasmid. Cytotoxic T lymphocyte (CTL) responses are also well produced as might be expected since the immune system is seeing what is a model of an infected cell. One important demonstration using a DNA vaccine has been the induction
of cytotoxic cellular immunity to a conserved internal protein of influenza A to determine if it
might be possible to overcome the annual variation (antigenic drift and shift) of the virus. CTLs were derived in
mice against the conserved flu nucleoprotein and this was effective at protecting
the mice against disease, even when they were challenged with a lethal dose of a
virulent heterologous virus with a different surface hemagglutinin. Because transfer
of anti-nucleoprotein antibodies to untreated mice does not protect them from
disease, the protective effect of the vaccine must have been cell-mediated. |
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The current influenza vaccine is an inactivated preparation containing antigens from the flu strains that are predicted to infect during the next flu season. If such a prediction goes awry, the vaccine is of little use. It is the surface antigens that change as a result of reassortment of the virus in the animal (duck) reservoir (see influenza). The vaccine is injected intramuscularly and elicits an IgG response (humoral antibody in the circulation). The vaccine is protective because enough of the IgG gets across the mucosa of the lungs where it can bind and neutralize incoming virus by binding to surface antigens. If a plasmid-based DNA vaccine is used, both humoral and cytotoxic T lymphocytes are produced, which recognize antigens presented by plasmid-infected cells. The CTLs are produced because the infected muscle cells present flu antigens in association with MHC class I molecules. If the antigen presented is the nucleocapsid protein (which is a conserved protein), this overcomes the problem of antigenic variation. Such an approach could revolutionize the influenza vaccine. Other studies have used a mix of plasmids encoding both nucleoprotein
and surface antigens. Protection by DNA vaccines has also been demonstrated with rabies,
mycoplasma
and Plasmodium yoelii.
Anti-HIV vaccines are also being tested. In the
HIV chapters, it was noted that
progress on AIDS vaccines has been stymied by the fact that many vaccines only elicit
humoral antibodies while the use of whole virus vaccines (which might elicit CTL
responses) has been rejected because of other potential problems. Plasmid-based
vaccines may overcome these problems |
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Figure 11
Vaccine-preventable diseases, by year of vaccine development or
licensure - United States, 1798-1998 (MMWR/CDC) |
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This page copyright
2009, The
Board of Trustees of the University of South Carolina
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