Interview with Ciro de Quadros, MD, MPH
The following is an interview with Ciro de Quadros, MD, MPH, director, International Programs, at the Sabin Vaccine Institute. This interview focuses on rotavirus vaccine advocacy, one of several international activities in which is engaged. The availability of a new rotavirus vaccine is much needed, especially for the developing world’s children.
SVR Dr. de Quadros, what are the factors that make rotavirus such a dangerous disease?
CdQ Rotavirus is the most severe of all the diarrheal diseases of children. Unlike many diseases that affect children only in developing countries, rotavirus is a democratic virus and affects children worldwide—rich and poor, black and white—without distinction. Consequently, every child is affected in the first few years of life. Why this first infection is so severe is unknown, but while most rotavirus diarrhea is mild, about ten percent of cases lead to dehydration requiring a doctor visit, and in developing countries one in 250 children will die from this dehydration.
SVR What factors make it so prevalent?
CdQ The fact that rotavirus affects children worldwide, in the United States and Bangladesh, for example, indicates that improvements in water and sanitation will not change the incidence of disease, but it is likely spread by other routes, such as airborne droplets or contact. It is highly infectious in low dose and spreads rapidly among children without prior exposure.
SVR Besides a vaccine, what precautions, if any, can be taken to prevent rotavirus?
CdQ We know of no way to prevent rotavirus infection but we do know that the disease can be made less severe if children are begun on treatment with oral rehydration when the first signs of vomiting and diarrhea begin. This strategy of early oral rehydration therapy will work for all acute diarrheal illness regardless of etiology, so while we can’t prevent rotavirus, we can prevent the development of severe disease that could lead to hospitalization or a fatal outcome.
SVR Who needs the rotavirus vaccine?
CdQ Every child in the world will be infected with rotavirus in the first few years of life and every child could benefit from a vaccine. In developed countries, rotavirus leads to doctor visits, hospitalization, lost parent workdays, and economic expense. In developing countries, the consequences of rotavirus can be fatal. A vaccine will serve to prevent severe disease in any setting—fatalities in developing countries, or hospitalizations and economic problems in developed countries.
SVR Your career in public health and disease eradication is impressive. What has been your experience with implementing efforts to address the rotavirus disease burden?
CdQ We have been working to assess the burden of rotavirus diarrhea in Latin America. Many studies of the importance of rotavirus have been conducted throughout Latin America over the past 20 years that indicate rotavirus is a major problem. Efforts are being initiated to set up sentinel hospital surveillance for rotavirus in many countries of Latin America, so the full extent of the disease burden can be further ascertained.
SVR Can you describe the general formulation of the vaccines that could potentially effectively prevent rotavirus? How will it be a better vaccine than the one that was used from 1998 to 1999?
CdQ Two vaccines to prevent rotavirus diarrhea are currently under development: one by GlaxoSmithKline (GSK) and another by Merck. The GlaxoSmithKline vaccine is based on a single strain of rotavirus isolated from a human with diarrhea and attenuated by repeated passaging in cell culture. It would be given as a live, oral vaccine in two or three doses to children at the time of their routine immunizations. The Merck vaccine will be based on a bovine strain of rotavirus that has been re-assorted and combined to provide protection against the four main serotypes of rotavirus in circulation, plus another outer capsid protein that is the most common target for virus neutralization. This vaccine, a live, oral vaccine as well, would be given in three doses.
SVR How would the vaccine be administered?
CdQ Both vaccines are live oral vaccines that would be administered orally at the time of the other routine childhood immunizations—to children 6, 10, and 14 weeks of age.
SVR We’ve heard about the small number of cases of bowel obstructions, or intussusception, that prompted the withdrawal of the previous vaccine. Is this the main hurdle to be overcome in developing the second-generation vaccine?
CdQ Early studies with the rhesus vaccine that was given to nearly one million children demonstrated that the vaccine was highly effective and relatively safe. It was withdrawn because of the rare adverse event of intussusception. In studying new vaccines, we would like to know that their risk of intussusception is less than the risk posed by the rhesus vaccine. This safety profile is the biggest hurdle to overcome in testing the next generation of vaccines. It requires that tests be conducted in more than 60,000 children to ensure that the rate of intussusception is less than one in 11,000. It also requires that investigators conducting trials have in place a mechanism to identify children with symptoms that might represent intussusception, which can be assessed and treated by a quality-care facility.
Since the new generation vaccines being tested are both live, oral vaccines, one might question whether it will be any better than the rhesus vaccine that was licensed in 1998. In fact, we won’t know the safety profile of these two vaccines until 60,000 children have been immunized and we can assess whether these children develop intussusception. Nonetheless, for the GSK vaccine, we have no evidence that natural human rotavirus is implicated as a cause of intussusception, so we hope that this holds for the vaccine as well. For the Merck vaccine, the bovine strains replicate less than the rhesus strains and cause less fever than the rhesus strains, meaning they are more attenuated. We hope that these milder infections will also be associated with fewer adverse events.
SVR There has been some controversy over the withdrawal of the 1998 vaccine because intussusception cases were few and the cases of children who die as a consequence of rotavirus are tremendously greater in number—between 600,000 and 800,000 per year. How does this dilemma impact the urgency of making a rotavirus vaccine available? Is the rotavirus vaccine a good case study on rethinking the benefit versus risk of vaccines, in general?
CdQ The risk-benefit analysis of rotavirus is quite different in developed and developing countries. In the United States, few children die of rotavirus and the disease is generally mild. Consequently, a vaccine with any adverse event poses an unacceptable risk. In developing countries where one in 250 children die of rotavirus, even a vaccine with a small risk of an adverse event could still be effective in preventing this most common cause of death in children. This is a true dilemma in vaccine delivery, with many economic, political and cultural overtones. However, with the trials ongoing and new vaccines preparing for future tests, we can develop a vaccine that is as effective as the first vaccine, but with a safer profile and fewer adverse events.
SVR I’ve heard that there can be different strains or serotypes of rotavirus. Are these different serotypes distributed geographically so that different kinds of cases would appear in say Latin America, than Africa or North America?
CdQ There are four or five main serotypes of rotavirus found worldwide. The vaccine—to be effective—must cover these principal serotypes. At the same time, the common serotypes in the United States are also common in Latin America and worldwide; however, in some countries like Brazil, unusual serotypes have emerged, perhaps from contact with cows or pigs, which also have rotavirus. Some evidence exists that genes of rotavirus of animal origin can re-assort and infect humans. These situations appear to be rare, but will require some monitoring of strains over time. Trials of the new vaccines are about to be conducted in many countries of Latin America, Asia, and the United States and Europe. At the same time, a vaccine has already been licensed in China and several other new vaccines could be licensed in India and Indonesia in five to seven years.
SVR How would this differentiation be addressed in a new vaccine?
CdQ The only way to know if a new vaccine will work against the main serotypes of rotavirus is to conduct large-scale field trials in a variety of settings. These studies are planned and will be ongoing shortly, and should give us an answer to these important questions in a couple of years.
SVR What about the clinical trials for a new vaccine? What will they entail?
CdQ Trials need to be large, with active follow-up for intussusception, and are relatively costly. It is unfortunate with rotavirus that we have no good proxy for protection from vaccine. Consequently, the only way to assess the efficacy of a new vaccine is through a large-scale clinical trial. Large-scale clinical trials of both the GSK and Merck vaccines are ongoing, so it conceivable that these vaccines could be licensed in two to four years.
SVR What is the global outlook for a vaccine once it is licensed?
CdQ Our hope for the global agenda is that in 10 years, we would be able to immunize 80 percent of the world’s children against rotavirus and decrease rotavirus mortality by 60 percent.
SVR Do you imagine rotavirus ultimately will be on the recommended childhood immunization schedule?
CdQ Absolutely, yes!