Effect of Buffer on the Immune Response to Trivalent Oral Poliovirus Vaccine in Bangladesh: A Community Based Randomized Controlled Trial 1

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 2Centers for Disease Control and Prevention, Atlanta, Georgia; 3Shimantik, Dhaka, Bangladesh; and 4Polio Operations and Research Department, World Health Organization, Geneva, Switzerland

Background. Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach acidity may neutralize vaccine viruses, we assessed whether administration of a buffer solution could improve the immunogenicity of tOPV. Methods. Healthy infants 4–6 weeks old in Sylhet, Bangladesh, were randomized to receive tOPV with or without a sodium bicarbonate and sodium citrate buffer at age 6, 10, and 14 weeks. Levels of serum neutralizing antibodies for poliovirus types 1, 2, and 3 were measured before and after vaccination, at 6 and 18 weeks of age, respectively. Findings. Serologic response rates following 3 doses of tOPV for buffer recipients and control infants were 95% and 88% (P = .065), respectively, for type 1 poliovirus; 95% and 97% (P = .543), respectively, for type 2 poliovirus; and 90% and 89% (P = .79), respectively, for type 3 poliovirus. Conclusions. Administration of a buffer solution prior to vaccination was not associated with statistically significant increases in the immune response to tOPV; however, a marginal 7% increase (P = .065) in serologic response to poliovirus type 1 was observed. Clinical Trials Registration. NCT01579825. Keywords. oral poliovirus vaccine; immunogenicity; serologic response; buffer.

Polio eradication efforts have been highly successful in most areas of the world, but circulation of wild polioviruses (WPVs) persists in some countries despite vigorous efforts and administration of multiple doses of polio vaccines to a high proportion of children [1]. The failure to eliminate WPV transmission in polioendemic countries is due in part to the lower immunogenicity of trivalent oral poliovirus vaccine (tOPV) in some countries [2]. Three doses of tOPV have induced >95% immune response rates for all 3 poliovirus types

Correspondence: Neal A. Halsey, MD, Institute for Vaccine Safety, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Rm W5041, Baltimore, MD 21205 ([email protected]). The Journal of Infectious Diseases® 2014;210(S1):S390–7 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected] DOI: 10.1093/infdis/jiu378


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in infants from industrialized countries, compared with 73% (range, 36%–99%) for type 1 poliovirus, 89% (range, 71%–100%) for type 2 poliovirus, and 70% (range, 40%–99%) for type 3 poliovirus in some developing countries [3, 4]. Factors known to affect the immune response to tOPV include vaccine potency, balance of type-specific poliovirus titers in the vaccine, errors in vaccine storage and handling, stabilizers, and maternal transplacental and breast milk antibodies [5, 6]. Other factors speculated to affect the response to tOPV (and other oral vaccines) include infant diet, altered intestinal integrity from recent infections, micronutrient deficiency (zinc), altered intestinal bacterial flora, intestinal coinfections with viruses or parasites, gastric acid, undefined genetic factors affecting the immune response, and maternal malnutrition, diet, and breast milk commensal bacteria [7, 8].

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Subhash Chandir,1 Kabir U. Ahamed,3 Abdullah H. Baqui,1 Roland W. Sutter,4 Hiromasa Okayasu,4 Mark A. Pallansch,2 Mark S. Oberste,2 Lawrence H. Moulton,1 and Neal A. Halsey1

The study was conducted from May through December 2012 in Zakiganj and Kanaighat subdistricts of Sylhet district, located in rural northeastern Bangladesh. The estimated population of the study site in 2011 was 501 106, with an average household size of 5.7 persons and a population density of 975 people/km2. The local population spoke Sylheti (a dialect different from the national language, Bangla), and their primary occupation was agriculture. Health services were delivered through public and private sectors, and nongovernmental organizations (NGOs). Vaccinations were provided by government and NGO immunization centers. The vaccines provided by the Expanded Program on Immunization (EPI) in Bangladesh included BCG, at 0–6 weeks of age; pentavalent (diphtheria-pertussis-tetanus, hepatitis B, and Haemophilus influenzae b) vaccine and oral polio vaccine, at 6, 10, and 14 weeks of age; and measles vaccine, at 9 months of age. According to the 2011 Demographic and Health Surveys, the overall vaccination coverage for routine EPI immunizations was 80%; coverage for 1 dose of tOPV was 95%, coverage for 2 doses was 93%, and coverage for 3 doses was 88%. Randomization

Enrolled subjects were randomized to receive the buffer or to serve as a control. The randomization sequence was created using SAS, version 9.3 (SAS Institute, Cary, NC), with a 1:1 allocation, using random block sizes of 2, 4, 6, 8, and 10. The allocation sequence was concealed from the medical officers who were screening and enrolling participants, using serially numbered, opaque, sealed envelopes. Vaccines and Intervention

METHODS Study Design and Participants

We conducted a community-based individually randomized controlled trial in Sylhet, Bangladesh. Participants were eligible if they were 4–8 weeks old at enrollment; resided in the study area; had not received any doses of OPV; had no known immunodeficiencies, neurologic disorders, or congenital malformations; and had not received blood products. We obtained written informed consent from parents at the time of enrollment. The study was monitored by a local safety monitor (a pediatrician) from the Bangladesh Institute of Child Health, who reviewed all adverse events. Initial reports of serious adverse events were reported within 24 hours, and final reports were submitted 5–7 days afterwards. The study was approved by the institutional review boards of the Johns Hopkins Bloomberg School of Public Health, the World Health Organization (WHO), and the Bangladesh Medical Research Council. The regulatory approvals were obtained from the Directorate of Drug Administration and the Ministry of Health and Family Welfare, Bangladesh. The trial was registered at (NCT01579825).

The buffer solution was manufactured and packaged by Beximco Pharmaceuticals (Bangladesh), contained 64 mg of sodium bicarbonate plus 24 mg of sodium citrate in 5 mL of sterile distilled water, and had a pH of 8.86. This buffer was prepared in individual unit dose containers with a shelf life of 2 years and was stored in a dry, locked cabinet at room temperature. Buffer was administered orally within 5 minutes before delivery of each of the 3 doses of tOPV. If a child vomited or spit out the buffer, another buffer dose was administered. The infants in the control arm received only tOPV; they did not receive placebo because anything given orally could have affected gastric pH and, hence, the vaccine response. All study participants received oral polio vaccines provided through EPI-Bangladesh. From May through August 2012, EPI administered Opvero (Sanofi Pasteur; batch H5210; expiration date, April 2013); each dose contained not less than 106.0 50% cell culture infectious doses (CCID50) of type 1 poliovirus, 105.0 CCID50 of type 2 poliovirus, and 105.8 CCID50 of type 3 poliovirus [16]. After August 2012, Polio Sabin (SmithKline Beecham Biologicals; batch AOPVB855AA; expiration date, June 2013) was administered. Each dose contained not less than 106.0 CCID50 of type 1, 105.0 CCID50 of type 2, and 105.8 CCID50 of type 3 [17]. OPV Buffer in Bangladesh

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Exposure to low gastric pH could reduce the viability of tOPV viruses. Poliovirus has been shown to be stable at a pH as low as 4.0; however, polioviruses are inactivated in 5 minutes at a pH of 1.0, in 15 minutes at a pH of 1.5, and in 4 hours at a pH of 2.0 [9]. Although there are no data on gastric acid and pH in infants from developing countries, studies from developed countries have shown that the gastric pH during the early months of life ranges from 2 to 4 [10, 11]. Administering an acid-neutralizing buffer at the time of each oral poliovirus vaccine dose could potentially enhance the survival of vaccine viruses in the stomach, increasing subsequent replication of vaccine virus in the intestine. A study in the United States found a beneficial effect of buffers (sodium bicarbonate in soybean formula or sodium bicarbonate plus sodium citrate in water) on the immunogenicity of tetravalent rhesus rotavirus vaccine [12]. In the same study, no differences were found in immune response to tOPV given with or without buffer for any of the polio serotypes [12]. Different types and amounts of buffers have improved the response to rotavirus and cholera vaccines [12–14], leading to the use of buffers with currently licensed oral vaccines, including Rotarix (GlaxoSmithKline Biologicals), Rotateq (Merck), and Dukoral (Crucell). A recent study in Thai infants found no significant difference in seroconversion rates between recipients of Rotarix vaccine reconstituted with calcium carbonate buffer and recipients of Rotarix vaccine reconstituted with water [15]. Since there were no controlled studies evaluating the potential effect of buffers on the response to tOPV in developing countries, we evaluated the effect of a buffer on the response to tOPV.



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variation. The samples with unobserved titers in starting and final dilutions were assigned values of

Effect of buffer on the immune response to trivalent oral poliovirus vaccine in Bangladesh: a community based randomized controlled trial.

Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach ...
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