This issue of The Scientist focuses on novel approaches to vaccines. Vaccines are “miracles” that have saved millions of human lives—more than any other medical intervention—by activating the body’s natural defenses to prevent infection. Likewise, veterinary vaccines protect our livestock and pets. Vaccines were originally produced to prevent infectious diseases, and this goal continues to be important. Today, however, there are also interesting developments in the use of vaccines to control noninfectious conditions, such as some types of cancer and Alzheimer’s disease, or, as discussed in this issue, cocaine addiction.
We still do not have sufficient insight into the reasons why certain vaccines work poorly or not at all.
Humankind has benefited from more than 200 years of successful vaccine use. (See time line.) One hundred years ago, parents worried most about their children contracting diphtheria, and 50 years ago they worried about polio; today, the most serious childhood infections have largely disappeared from the developed world. Moreover, the World Health Organization officially declared the global eradication of smallpox in 1980. In addition, vaccines are now available to combat adult diseases such as cervical cancer and shingles. Yet there are three major 21st century scourges that still cry out for efficacious vaccines: HIV/AIDS, tuberculosis, and malaria.
Prevention is better than cure
Since ancient times, people have realized that you could only catch certain diseases once. If you recovered, you became immune for the rest of your life. In the 17th century, variolation—scratching a small amount of a patient’s smallpox scab into the skin of uninfected individuals, inducing a mild form of the disease followed by protective immunity—was introduced to Europe from China by way of Turkey. Although around 1-2 percent of variolated people contracted the disease and died, the odds were still favorable during a raging epidemic. In 1796, Edward Jenner took note of the folk observation that milkmaids had smooth complexions: they did not get smallpox. (In the nursery rhyme that begins “Where are you going, my pretty maid?/ I’m going a-milking, sir, she said,” the girl claimed that “My face is my fortune” because it was free of pockmarks.) Jenner successfully used the relatively harmless cowpox as a vaccine (from the Latin vacca, “cow”) in place of smallpox.
Although we understand the immune system better today, we still do not have sufficient insight into the reasons why certain vaccines work poorly or not at all, or why some of the most successful ones (e.g., the vaccine against yellow fever) protect for a lifetime. Rather than targeting the pathogen itself, some vaccines protect against the byproducts of infection, such as the toxins produced by diphtheria and tetanus bacteria. In the 90 years since the Bacillus Calmette-Guérin (BCG) vaccine—made from bovine TB—was developed to fight the Mycobacterium that causes human tuberculosis, there has unfortunately been little progress in developing a new vaccine. But promising results are beginning to emerge for a vaccine that may offer partial protection against the malaria parasite. HIV has managed to evade researchers’ best efforts towards an efficacious vaccine: the virus rapidly changes its outer coat, and protects itself with a “glycan shield” or sugary carapace. Moreover, HIV invades and subverts the immune system itself. Gene Shearer and Adriano Basso resurrect an approach to HIV immunization based on using human antigens in addition to viral antigens. But a pathogen’s immune-evasion strategy is not always the biggest barrier to vaccine development. As Brad Spellberg discusses, investment in the development of fungal vaccines has been hindered by the lack of demand in the developed world and by a perceived lack of profitability.
Although vaccines were originally designed as a method of preventing disease, we now realize that stimulating the immune system after diseases have taken hold may also help patients. Therapeutic (rather than prophylactic) vaccines have been designed to make cancer cells look more foreign so that immune cells will destroy them. But because cancer cells originate from our own cells, there is danger that such an approach could backfire, with the body rejecting its own tissues in an autoimmune reaction. Paradoxically, the very immune reaction responsible for transplant and graft rejection may help to spawn a new kind of vaccine, as Shearer and Basso explain in their article. Therapeutic vaccines are also being attempted for conditions like addiction. Although molecules of nicotine and cocaine are too small to elicit immune reactions by themselves, Thomas Kosten writes about the development of a vaccine against cocaine that couples an immune-stimulating protein to the small addictive molecule.
The future of vaccines
Despite the enormous number of lives saved by immunization, a vocal minority holds the view that these measures are harmful. Parents who withhold vaccination from their children usually see no ill effect, because they benefit from the vast majority of vaccinated children providing “herd immunity,” making the disease agents much rarer. Sadly, though, because of the unjustified scare about a vaccine-autism link—a claim which is not evidence-based and which has been rejected by public-health authorities—we have witnessed a rise in measles infections, which can have debilitating complications. One of the greatest challenges of the modern era is to convince parents in Western countries of the essential benefits of vaccines. With the exception of a few brave individuals, the scientific community as a whole has not risen to this challenge.
If only this vocal minority could appreciate the enormous impact vaccines have had in the past and their untapped potential for the future. For example, there is the challenge of developing an efficacious multivalent influenza vaccine that would avert pandemic influenza. Rino Rappuoli outlines the extraordinary challenges inherent in developing “universal” vaccines, protective against all strains of rapidly replicating viruses such as influenza and HIV. These viruses mutate key proteins at a furious rate, reconfigure their shapes, and recombine with each other, constantly evolving to make it harder for the immune system and vaccinologists to find a highly conserved Achilles’ heel. Further problems concern the huge cost of manufacturing, the growing complexity of vaccine design, the fear of liability on the part of pharmaceutical companies, and the funding and logistics of rollout in countries where vaccines are most needed. Yet given determination, these challenges can be surmounted.
Robin A. Weiss is a professor of viral oncology at University College London. Peter Hale is the founder of the Foundation for Vaccine Research, Washington, DC.
Editor's Note: The time line appearing in the online version of this article has been corrected and amended. The Scientist regrets these oversights.