Members of the Malawi field team who visited pregnant women monthly to check on status of pregnancy and encourage them to go for pre-natal visits
This post originally appeared on Johns Hopkins' The Globe.
A new study by a team of Hopkins faculty and students led by Dr. Mohammad Ali, a senior scientist in International Health, found significant evidence that the oral killed whole-cell cholera vaccine is safe to administer during pregnancy.
Cholera affects about 2.5 million people a year, and, if untreated, the disease can be fatal in a matter of hours. As a result, around 100,000 people—overwhelmingly the world’s most vulnerable—die every year because they have no access to care (1). Among pregnant women, cholera can increase the risk of miscarriage and stillbirth by up to 36 percent. Yet, pregnant women have largely been excluded from vaccination campaigns because little evidence has been available to confirm that it is safe for fetuses (2) —leaving both the women and their pregnancies less protected from the disease.
Cholera vaccine manufacturers currently advise against the use of the vaccine among pregnant women. The World Health Organization (WHO), however, recommends that pregnant women at high risk for cholera receive it. The disconnect lies in the amount of evidence and concerns about liability. Inactivated, or killed, vaccines especially when given orally, are generally not expected to pose an elevated risk to the fetus. Killed vaccines, such as the ones used against influenza and tetanus toxoid, are widely recommended for pregnant mothers across the world and have helped reduce mortality among mothers and newborns. But pre-licensure trials of even killed vaccines typically do not include pregnant women, in case the vaccine does cause unexpected adverse outcomes. Because the cholera vaccine has not been in wide use until the last decade, there has been relatively little opportunity to test its safety during pregnancy.
After recent vaccination campaigns, researchers have been able to conduct several retrospective studies to evaluate the safety of the vaccine during pregnancy. These studies rely on data from the women who inadvertently received the vaccine because they didn’t report being pregnant. Findings consistently point to the vaccine’s safety for fetuses. However, the evidence has not been enough to convince the vaccine manufacturers, fearful of litigation, to change their recommendations. As a result, programs and governments have frequently chosen not to vaccinate pregnant women.
2015 Malawi Cholera Outbreak
In January 2015, cholera cases were being reported across Malawi after widespread flooding. Based on the slowly building evidence that the vaccine was safe during pregnancy, the Malawi Ministry of Health, in consultation with the WHO, planned for a mass vaccination program, which would include pregnant women. Unfortunately, there was not enough vaccine available to cover all affected regions. A decision was made to cover everyone age eligible in Nsanje district, which was the hardest hit at the time. In the neighboring district of Chikwawa, where the risk of the disease was lower, the vaccine would not be offered.
The Delivering Oral Vaccine Effectively (DOVE) Project
Dr. Ali is a member of the International Health’s Delivering Oral Vaccine Effectively (DOVE) Project, which is supported by the Bill & Melinda Gates Foundation and based in the Bloomberg School. As its name suggests, the DOVE Project funds and conducts research to answer questions on how to improve the delivery of cholera vaccine. “When our project heard about Malawi’s vaccination plan, we quickly submitted a proposal to the government of Malawi and the WHO asking permission to set up a study,” says Dr. Ali. “The situation in Malawi allowed us to propose what would be the first prospective study on this issue. Findings from such a study could provide much stronger evidence than any earlier research. After the Malawi government and the WHO approved the study, Allyson Nelson, who was an MSPH student in the Department’s Global Disease Epidemiology and Control Program, relocated to Malawi for several months to manage operations on the ground.
"We couldn’t have done it without Allyson’s skill and dedication to the project,” says Ali. “Working closely with Malawian colleagues and other scientists in the DOVE Project, and in collaboration with the Johns Hopkins Project in Blantyre, she was involved in every aspect of the study—from field training and survey development to managing data collection and analysis."
The study enrolled nearly 1,800 pregnant women, and half of them received the vaccination. Research analyzed the following outcomes:
· Pregnancy loss (spontaneous miscarriage or stillbirth)
· Neonatal deaths
· Newborn malformations
The study’s success was made possible through a network of collaborator both in the US and Malawi. “We are very thankful for the excellent collaboration with the health officials and scientists in Malawi as well as the research resources developed by the Department of Epidemiology (especially Dr. Taha) in Blantyre," explains Dr. David Sack, a professor in International Health and the director of the DOVE Project. “Working together, it was possible for Dr. Ali and Allyson Nelson to conduct this very important study which will benefit vulnerable people around the world.”
Allyson Nelson with data collection team members traveling to communities inaccessible by road after the widespread flooding in Malawi in 2015
Findings and Implications
The study found no significant increase in risk of adverse outcomes in pregnancy or in neonatal deaths or newborn malformation. As a result, the study authors recommended that pregnant women in cholera-affected areas should receive the vaccine. Although the findings were only published in February of this year, other cholera vaccine experts have already acted on the findings, explains Ali:
Based on our study, WHO’s scientific advisory group for oral cholera vaccine reported that there is enough evidence to safely administer the vaccine without regard to pregnancy status (3). I’m hopeful that WHO will take this advice and strengthen its current recommendation in favor of vaccination during pregnancy.
While this study marks a major advance for the delivery and access of the cholera vaccine, Ali and his colleagues in the DOVE Project still have important questions left to answer. They hope to next look into the optimal dosing schedule for the vaccine. Currently, two doses are recommended over a two-week period. The timing has proven a logistical problem for many programs. The DOVE team would like to look into longer dosing intervals and the long-term effectiveness of a single dose—both of which could significantly reduce implementation barriers and improve access for vulnerable populations.
The study, "Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort study," was published 01 February 2017 in the Lancet Infectious Diseases. The authors were Mohammad Ali, Allyson Nelson, Francisco J Luquero, Andrew S Azman, Amanda K Debes, Maurice Mwesawina M’bang’ombe, Linly Seyama, Evans Kachale, Kingsley Zuze, Desire Malichi, Fatima Zulu, Kelias Phiri Msyamboza, Storn Kabuluzi, David A Sack.
1. Updated Global Burden of Cholera in Endemic Countries. Mohammad Ali , Allyson R. Nelson, Anna Lena Lopez, David A. Sack. PLOS NTD Published: June 4, 2015 https://doi.org/10.1371/journal.pntd.0003832
2. Safety of Immunization during Pregnancy: A review of the evidence, WHO 2014
3. Background Paper on Whole-Cell, Killed, Oral Cholera Vaccines Prepared by the SAGE Working Group on Oral Cholera Vaccines, the World Health Organization (WHO) Secretariat, and the Centers for Disease Control and Prevention March 31, 2017. Retrieved May 1, 2017 (http://www.who.int/immunization/sage/meetings/2017/april/OCV_Background_...)