The year is 1796. Smallpox is stalking England. A fearsome killer, the speckled monster, as the disease is known, will kill at least one person in ten — even more in the crowded cities and towns where the infection spreads like wildfire.
Once smallpox has taken hold, there is no treatment and no cure. Starting with fever and vomiting, the patient soon develops a terrible rash which evolves to deep blisters. A third of those who develop the disease will die — of blood poisoning, secondary infections or internal bleeding. The survivors are often horribly scarred.
Gloucestershire surgeon Edward Jenner knows smallpox well. He has seen many people succumb to the disease and was lucky to survive it himself. He is also aware of a curious fact: people who contract cowpox, a mild viral infection of cows that can spread to humans, seemed never to catch smallpox.
In May 1796, milkmaid Sarah Nelmes consults Jenner about a rash she has developed on her hand. Jenner diagnoses cowpox after confirming that Blossom, one of the cows Sarah milks, has recently shown signs of the disease.
Jenner decides to conduct an extraordinary experiment which will change the course of medical history: he calls James Phipps, the eight-year-old son of his gardener, into the surgery. After making some scratches on James’s arm, Jenner rubs in some material from Sarah’s rash. Within a few days, James becomes ill, but is well again a week later.
Jenner calls young James back into his rooms and again scratches his arm, this time rubbing some smallpox-infected material in. Much to Jenner’s excitement (and to James’s relief) the boy does not develop smallpox, even after repeated exposure to the virus.
It is probably worth noting at this point that in 1796, physicians had a rather different concept of medical ethics to what is considered acceptable today. But Jenner’s discovery of vaccination — from the Latin word vacca, cow — made the control of smallpox possible.
In 1980, almost 200 years and several million vaccinations later, the World Health Organisation announced that medical science had succeeded, for the first time, in completely eradicating a disease.
How vaccines work
Jenner’s experiment worked because, although it is a different organism, the cowpox virus (vaccinia) is genetically very similar to the smallpox virus (variola). Having encountered cowpox, James’ immune system was also prepared to deal with smallpox when it came along.
Vaccines work by tricking the immune system into thinking they have already encountered a microorganism; if that organism does come a-knockin’, the immune system ‘memory’ is primed and ready to dispatch it before it takes hold.
This is organised mostly through a class=“glossary-term” href=”/glossary/term/409”>B-cells, which respond to infection by making antibodies, microscopic Y-shaped molecules that attach themselves to and neutralise viruses, bacteria and other antigens in the bloodstream.
By bringing into the body an immunogen (an antigen that generates an immune response) which doesn’t cause disease but is physically similar to a specific disease-causing organism (pathogen), vaccination prepares the immune system for future exposure to that pathogen, enabling the body’s own defences to defeat it before disease takes hold.
Each B-cell in the body is programmed to respond to specific antigens. But once the B-cell encounters one of those antigens and is activated, as well as producing antibodies it creates many duplicate copies of itself, in readiness for a future attack. Because they provide a long-lasting memory of previous immune response, these duplicate B-cells are sometimes called memory cells.
Vaccines which produce only a weak immune response sometimes require several booster doses given over a period of time; sometimes the booster shot is a different vaccine — this is called a prime-boost approach.
Therapeutic vaccines
Not all vaccines are designed to prevent infection. A promising area of HIV research is the development of therapeutic vaccines against HIV. Therapeutic vaccines differ from preventive (or prophylactic) vaccines in that they are given to people already infected with HIV.
Because HIV attacks the immune system itself, the body’s initial response to the virus falls off quickly after infection. A therapeutic vaccine would stimulate the immune system to restore that response.
Quite a number of experimental therapeutic vaccines have already been tested in people with HIV. Although in some cases research showed that the vaccines did stimulate the immune system to respond (they were immunogenic), none of the vaccines appeared to have any clear impact on HIV replication.
To date, therapeutic vaccine research has focused mostly on four key HIV proteins — two from the virus’s coat (gp120 and gp160) and two from the virus’s core (p24 and p17). Although people infected with HIV will already have an immune response to these proteins, the theory is that by introducing them in a different way the immune response might be augmented. An example of an existing vaccine that works the same way is the rabies vaccine, which is administered after infection to stimulate an immune response.
One experimental therapeutic vaccine that was tested in the early 1990s was rgp160, developed by a company called Genentech. Although it appeared to work in animal studies, rgp160 did not show any impact on disease progression in infected people. This vaccine was later sold to another company, VaxGen, who are now testing a modified version of it, called AIDSvax, as a preventive vaccine. Other therapeutic vaccines which have proven uninspiring in clinical trials include British Biotech’s P24-VLP and Immune Response Corp’s Remune.
Several new therapeutic vaccines are in development, including one, DermaVir, which is applied to the skin. Therapeutic vaccines are likely to have the greatest benefit as a treatment for people recently infected with HIV.
Preventive vaccines
There and there are several different ways to make a preventive HIV vaccine, each with its pros and cons.
An inactivated vaccine could be made by killing the virus with chemicals or heat. Your annual ’flu shot is an example of this type of vaccine, as are the vaccines for hepatitis A, cholera and bubonic plague. The good thing about these types of vaccines is that, because the pathogen is dead, they are generally very safe to take. Unfortunately, research into a “whole killed” HIV vaccine has proven disappointing, as the virus tends to disintegrate when killed.
Live, attenuated vaccines contain a modified, but live, version of the disease-causing organism. Because there is a possibility that the organism can revert to a disease-causing form, these vaccines are often not recommended for people with compromised immune systems; for the same reason it is unlikely that an HIV vaccine made this way would be safe. Yellow fever, polio, rubella, measles and mumps are examples of this type of vaccine.
The development of genetic engineering has enabled new and second-generation vaccines to be developed. Much of the current research into HIV vaccines (both preventive and therapeutic) focuses on this area.
By identifying the specific proteins by which the immune system recognises HIV, scientists hope to create a vaccine using just the tiniest fragment of HIV’s genetic material to trigger an immune response to the virus.
Recombinant vector vaccines work by inserting fragments of genetic material from HIV into a separate vector microorganism which has been weakened or does not cause disease in humans. Although the vector doesn’t contain enough of HIV’s genetic code to cause disease, it expresses the HIV genes on its surface, triggering the immune response. The canarypox, fowlpox and cowpox viruses are all being investigated for use as vectors in this way.
Why is it so hard to make an HIV vaccine?
The development of an effective HIV vaccine has proven particularly challenging because of the way in which HIV continually mutates and changes into new forms. This is also a problem with other viral diseases but in HIV it has proven especially troublesome. An HIV vaccine will have to protect against many different strains of HIV, whereas most vaccines protect against just one or a few. Because of this, it’s likely that any future HIV vaccine will be only partly effective.
Additionally, because HIV infects CD4 cells, the cells which drive the immune response once a pathogen has been detected, an HIV vaccine would have to activate the very cells that HIV infects.
Nonetheless, research into finding an effective HIV vaccine is proceeding at an ever-increasing rate. With more than 20 candidate HIV vaccines in clinical trials and with many more in pre-clinical development, vaccines are likely to be increasingly in the news in the months and years ahead.
Blossom would be pleased.
