When There Is No Vaccine

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Passive immunization is the answer.

Author: Jack Woodall

In 1942, long before the vaccine was available, I contracted measles, went into a coma, but recovered. My younger brother and sister received transfusions of immune serum from our mother, who had had measles as a child, and were protected. My siblings were not the only ones to benefit from serum treatment: In 1970, two people working on Lassa fever at a university research lab caught the illness, and one died. The other was diagnosed in time, received immune serum from a Lassa survivor, and recovered.

Vaccines have saved countless lives. But there are still diseases that cause large numbers of cases and deaths, such as dengue and malaria, for which vaccines have been sought for decades but always seem to be five years in the future. Other important diseases like Ebola and Lassa fevers are crying out for vaccines, which are under development but still predicted to take years before they will be generally available.
Apart from transfusion with immune serum from survivors, specific treatments were actually available for many diseases before the era of antibiotics and modern vaccines. Among the most effective was serum therapy with antitoxins and toxoids produced in horses against diphtheria, tetanus, and other diseases. The use of equine serum survives today in the treatment of human botulism; the US Centers for Disease Control and Prevention holds an emergency supply of trivalent equine antitoxin, released to treat the rare human cases that occur annually.

Human convalescent serum has been used to treat Lassa fever patients in West Africa; the results are controversial but the therapy merits further testing. To date, not enough Ebola fever patients have so far been treated with the extremely rare convalescent serum (there aren't many survivors) to draw any conclusions about the efficacy of passive immunization in that disease.

But there are diseases for which we know passive immunization works. Why hasn't the serum of millions of dengue convalescents been pooled and the dengue immunoglobulin extracted, just as rabies immunoglobulin is produced from the serum of vaccinees? Why hasn't the same been done with serum from malaria immune people?

It's not because of the known limitations of horse serum. In some people it produced serum sickness (an allergic reaction), so the therapy could not be used on everyone. However, years ago Soviet labs developed a method to purify it, and their horse serum has been tested by the US military and did not cause serum sickness in human volunteers.

Lassa fever virus sickens thousands of people and kills many in Sierra Leone, Liberia, and elsewhere in West Africa every year, and still no vaccine exists. Junin virus causes Argentine hemorrhagic fever in people who harvest wheat in northern Argentina. Although a vaccine exists, specific treatment is still needed for unvaccinated people who become ill, or because of vaccine failure. These two viruses are arenaviruses, the group to which the agents that cause Brazilian, Bolivian, and Venezuelan hemorrhagic fevers also belong. A therapy that targets this whole virus group could save many lives.

Virus infections each produce a specific immune response, and a subsequent infection by a virus of the same group produces not only a specific response to itself, but also a boost in immunity to the first. Therefore, because of these cross-reactions, a horse serially immunized against only two or three different viruses could produce a serum effective to treat a whole range of hemorrhagic fevers.

So, all the pieces are in place to produce a broad-spectrum arenavirus antiserum, which could save many lives while specific vaccines are being developed and certified. This path of proven technology to produce equine antisera could lead to licensed passive immunization products faster than the new generation of bioengineered vaccines, and offer valuable protection in the interim.

There is just one bureaucratic snag. US Food and Drug Administration rules promulgated in 2002 have stopped cold the progression to market of any new therapeutic product targeting a disease for which it is not ethically admissible to carry out human trials. What is widely known as the "two-animal rule" requires that instead, the product be tested in at least two different species, one of which should ideally be a non-human primate. As this requires Biosafety Level 4 animal containment facilities, the cost of complying with this measure outruns even the astronomical cost of human trials.

Jack Woodall is director of the Nucleus for the Investigation of Emerging Infectious Diseases in the Institute of Medical Biochemistry at Brazil's Federal University of Rio de Janeiro.