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How to Build a Better Vaccine

Polio, diphtheria, measles, smallpox. Each a scourge through the ages; each now preventable because of a vaccine. Medical science has scored considerable successes in developing these guardians of health, saving millions of lives each year. For every vanquished pathogen, though, many more lurk.

Illustration: Wesley Bedrosian

The challenges for vaccinologists are enormous. The ideal vaccine keeps resistance high for a long time, preferably a lifetime. It is safe and free of side effects, effective as a single dose, stable, and affordable, even for vulnerable populations in the developing world. Clearing this high bar may seem impossible, especially when the time factor is considered: Vaccines often require a decade to develop and an additional decade to test for safety and efficacy.

For more than 200 years, ever since Edward Jenner famously used cowpox to inoculate a boy against smallpox, vaccines have relied on pathogens that are alive yet weakened or “killed.” But according to Darren Higgins, an HMS professor of microbiology and immunobiology, advances in laboratory technologies—combined with breakthroughs in such fields as genetics—are shaving years off discovery. And new ways of thinking about testing vaccines promise to save time without sacrificing purpose. Here Higgins outlines key steps to building better vaccines for new adversaries.

1. Unmask your foe.

First things first: Determine why people are getting sick. Perhaps a noxious chemical is causing harm, or an environmental agent is triggering cancer. To finger an infectious cause, you must scrutinize symptoms. Do they appear in nearly everyone who has fallen ill? If an agent is infectious, how might it be spreading?

2. Divide and conquer.

To help nail down the cause, collect samples for analysis. Blood, sputum, and even the revisited remains of a semi-digested meal may hold a clue to the causative agent. Staining blood samples can bring to light bacteria and even break them into classes that might respond to antibiotics. Vaccinologists are increasingly turning to polymerase chain reaction, or PCR, a technique that zeroes in on genetics—and can pare months, even a year, off the search for a pathogen.

3. Locate next of kin.

Study the PCR and DNA sequence analysis for familiar features. The malefactor responsible for the recent SARS outbreak, for example, was found to be genetically related to coronaviruses, for which an effective antiviral existed. Is there a gene you can silence, thereby undoing the disease agent? If the relatives are bad but not deadly, a vaccine may not be the answer. Rhinoviruses go unchallenged in part because colds are tolerable. But for potentially deadly influenza viruses, vaccines are reformulated annually.

4. Build your armor.

Ponder for a moment the merits of vaccine type: therapeutic or preventive? Preventive vaccines have tended to rule. All childhood immunizations are designed to block their respective disease; vaccines for adults are, too. But the new wave is the therapeutic vaccine, one that boosts the immune system to lessen symptoms, such as the vaccine being developed for herpes simplex virus type 2. If the agent uses a toxin to cause disease, you can deactivate it and spur immunity with a toxoid vaccine.

5. Choose your weapon.

More is better: Vaccines that stimulate both arms of the adaptive immune system—B and T cells—represent the new ideal for vaccinologists. Conjugate vaccines are one example. Certain subunits trigger antibody production by stimulating B cells, white blood cells that recognize foreign invaders. Other subunits spur helper-T cells and their killer cousins to recognize and eliminate pathogen-infected cells. Genetic insights into the interloper can direct or update subunit formulations and may one day allow physicians to customize vaccines to suit pathogen and patient.

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