How to Make A Vaccine

In the 1770s, British physician Edward Jenner began noticing a strange phenomenon.

It was known that milkmaids sometimes caught a disease from the cows, called "cowpox," similar to smallpox in the red boils it produced, but not nearly as dangerous. More importantly, once milkmaids had recovered from cowpox, they seemed to be immune from smallpox.

After studying the problem, Jenner eventually developed a relatively safe and effective method for "vaccination," from the Latin root of vacca, for cow. Breaking open swollen blisters from the milkmaids' hands, Jenner produced a primitive vaccine and injected it into the arms of his patients.

It worked in 1796. And less than two hundred years after Jenner's first vaccine, doctors can claim to have completely wiped out smallpox infections.

Over the next century, scientists such as Louis Pasteur, Robert Koch and Paul Ehrlich developed more vaccines to diseases such as diphtheria, in the process saving countless millions of lives.

But how did scientists get there? What properties of the body's immune system allow such careful engineering to work? And what goes into making a vaccine?

The job of a vaccine is to impart immunity against a given disease to a person by educating the immune system. The idea is to expose a person to an antigen without causing the full-blown effects of the disease normally associated with it.

Thanks to the immune system's capacity for memory, when the individual encounters the virus or bacteria later on in their lives, their immune system can respond quickly and efficiently to prevent the disease.

Such memory is generated on the basis of interactions between specialized cells, known as T and B lymphocytes, and antigens. Upon first "seeing" a given antigen, in the phase known as the "primary response," just a handful of the millions of cells can actually recognize, or bind, the antigen. The system is thus incapable of mounting a truly effective response.

But upon subsequent infection with the same antigen, the immune system leaps into action against the already familiar enemy, and immobilizes it with a much stronger "secondary response."

The trick for vaccine designers is to find an antigen which fools the immune system into thinking it is a dangerous foe, but is actually a harmless look-alike.

The Shots Hurt Around the World

Realizing this, in the early 1950s, Dr. Jonas Salk used injections of dead polio viruses as a vaccine against the crippling and sometimes fatal disease, which rose to epidemic proportions each summer to strike victims such as Franklin Delano Roosevelt '04. On April 12, 1955, U.S. health officials proclaimed the vaccine a success.

Today, research into the production of new vaccines is a major undertaking, involving academic researchers, government agencies, and pharmaceutical and biotechnology firms all working to provide newer and safer prevention of disease by infectious agents, allergens, and even some forms of cancer.

Physicians use vaccines against viruses, such as the measles, polio, mumps, or rubella, against bacteria, such as typhoid and salmonella, and against bacterial toxins, such as pertussis, tetanus and diphtheria. Each type of antigen, however, requires its own strategy.

"Traditionally with viruses the classic approach has been to either inactivate the virus, which is basically taking a live virus and adding chemicals to is that make it inert," says Dr. Bernard N. Fields, Lehman professor of microbiology and molecular genetics at the Medical School. "Or alternatively you can weaken the virus."

Such weakened, or attenuated, viruses, can be used as live viral vaccines which grow in the host, stimulate immunity, but don't cause the disease, says Fields.

Some of the newest techniques actually require no virus, either dead or alive, at all. Scientists simply take advantage of the antigens themselves, injected free of their dangerous viral carriers, to provoke an immune response. When a given antigen shows up again, this time on a virus, it's as if the immune system has already seen the whole virus.

But Associate Professor of Tropical Public Health Donald A. Harn, who works on vaccines against the tropical disease schistosomiasis, says that finding the right antigen when attempting a recombinant vaccine, as they are known, "is the most critical and difficult thing to do."

Harn says that one problem researchers face is that the immune system often fails to respond to such isolated antigens. Simply finding an antigen present in or on the virus is not sufficient. To boost the response, solutions known as adjuvants are included in the injection of the antigen.

While creating recombinant vaccines doesn't always work, scientists can take hope in one success, a recombinant vaccine against the Hepatitis B virus.

Scientists are continually striving to perfect new strategies and techniques to create new viruses. But in order for the vaccines to be effective, they must be mass-produced and distributed.

Most vaccine production is carried out by five major pharmaceutical companies: Merck, Smith-Kline Beecham, Connaught, Merieux and Medeva. But according to Dennis Panicali, president and CEO of the Cambridgebased Therion Biologics Corporation, it's the small biotechnology firms which are experimenting with more novel techniques for producing vaccines.

"Biotech companies have a role in being able to accept a greater risk," Panicali says. "Large pharmaceutical companies cannot assume [as much risk] because of their obligations to their stockholders."

The biotech firms and pharmaceutical companies also work in conjunction with university based researchers. Panicali said his company has worked in conjunction with investigators at Harvard, the University of Massachusetts and Ohio State University.

According to Fields, very few labs at the Medical School work directly on vaccines. Field's work in basic science, for example, is in studying pathogenesis, the mechanisms by which an infection occurs and spreads.

Dr. George R. Siber, an associate professor of medicine, is a busy man on both sides of the vaccine development arena. As a researcher at the Dana Farber Cancer Institute, Siber works at finding keys to new vaccines. But as director of the Biological Laboratory division of the Mass. Department of Public Health, Siber oversees the manufacture and distribution of several of the most widely used vaccines to doctors and clinics at no cost.

The laboratory was founded in 1894 when most vaccine production went on in public state labs, rather than in private companies. Currently, Siber said, Michigan is the only other state still actively producing vaccine.

But Siber says that many of the products of his state lab go unused, especially by adults. "As a rule, 80 percent of [adults and elderly] who deserve [these vaccines] don't get them because of our lack of awareness," he says.

Despite the long hours, Siber seems he is happy to continue the legacy of Jenner and Salk.

His work is "the world's best job," says Siber, because of the number of people whom he can help. "The return on the dollar is 10 to one," he says.