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Safety and immunogenicity of a booster dose of meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine

Tuesday, 1st of November 2016 Print

Vaccine, Volume 34, Issue 44, 17 October 2016, Pages 5273–5278

Safety and immunogenicity of a booster dose of meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine

Corwin A. Robertsona, , ,

David P. Greenberga, b, ,

James Hedrickc, ,

Michael Pichicherod, ,

Michael D. Deckera, e, ,

Martha Saundersf,

a Scientific and Medical Affairs Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370, USA

b Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

c Kentucky Pediatric/Adult Research, 201 South 5th Street, Bardstown, KY 40004, USA

d Legacy Pediatrics, 1815 South Clinton Avenue, Suite 360, Rochester, NY 14618, USA

e Department of Health Policy, Vanderbilt University School of Medicine, Nashville, TN 37212, USA

f Huguenot Pediatrics, 1407 Huguenot Road, Midlothian, VA 23113, USA

Received 29 April 2016, Revised 4 August 2016, Accepted 4 September 2016, Available online 15 September 2016


Highlights

• Waning immunity within 5 years of a primary dose of MenACWY has been documented.

• MenACWY-D administered after a prior dose was safe and induced booster responses.

• The results support current ACIP recommendations on MenACWY use in US adolescents.


Excerpt below; full text is at http://www.sciencedirect.com/science/article/pii/S0264410X1630799X

Background

Quadrivalent meningococcal conjugate vaccines (MenACWY) were developed to offer long-term protection against invasive disease caused by serogroups A, C, W, and Y. Reduced MenACWY effectiveness within 5 years after primary vaccination (likely due to declining bactericidal antibody titers) has been described, particularly with respect to C and Y disease in the United States. We evaluated the safety and immunogenicity of a single booster dose of quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) in adolescents and adults who received a previous dose 4–6 years earlier.

Methods

This phase 2, open-label, multicenter study of 834 persons was conducted in the United States. Participants received a single 0.5-mL booster dose of MenACWY-D. Serogroup-specific bactericidal antibody geometric mean titers (GMTs) were measured with a serum bactericidal antibody assay using human complement (hSBA). Proportions of participants achieving antibody titers of 1:8 for each vaccine serogroup on Days 6 and 28 were determined. Rates of adverse events (AEs), including serious adverse events (SAEs), were also assessed.

Results

Before booster vaccination, 38.7–68.5% of participants had an hSBA titer 1:8, depending on vaccine serogroup. By Day 6 post-vaccination, 98.2–99.1% of participants had hSBA titers 1:8. By Day 28, >99% of participants achieved this threshold and the primary hypothesis (lower limit of the one-sided 95% confidence limit 85% for each serogroup) was met. The GMT ratios (post-vaccination divided by pre-vaccination) at Day 28 ranged from 47.2 (serogroup A) to 209.1 (serogroup Y). Rates of AEs, including SAEs, were similar to those observed among adolescents and adults who received a primary dose of MenACWY-D in previous studies. There were no study discontinuations due to an AE and no deaths.

Conclusions

Booster vaccination with MenACWY-D was safe and induced robust bactericidal antibody responses, consistent with immune memory, among adolescents and adults 4–6 years after primary vaccination.

ClinicalTrials.gov registration: NCT01442675.


1. Introduction

The aerobic gram-negative diplococcus Neisseria meningitidis is a leading cause of bacterial meningitis, with the most common presentation of invasive meningococcal disease (IMD) being purulent meningitis [1]. Meningococcal sepsis without meningitis occurs in 5–20% of cases of IMD [1]. The overall case-fatality ratio for meningococcal disease is 10–15%, while meningococcal sepsis is fatal in 40% of cases [1]. Up to 10% of adolescents and adults are transient asymptomatic carriers of meningococci, and transmission is primarily through the exchange of nasopharyngeal secretions from colonized or infected individuals [1]. Although at least 12 meningococcal serogroups have been identified on the basis of structural differences in the capsular polysaccharide, only five (A, B, C, W, and Y) have been primarily responsible for IMD worldwide, while a sixth serogroup (X) has emerged since 2006 as an important cause of IMD in Africa [1], [2], [3] and [4].

Prior to the introduction of the serogroup A meningococcal polysaccharide-tetanus toxoid conjugate vaccine in sub-Saharan Africa in 2010, an estimated 1.2 million new cases of IMD occurred globally each year in both endemic and epidemic forms, resulting in approximately 135,000 deaths [5]. In the United States, provisional surveillance estimates for 2014 indicate a total of 450 cases of meningococcal disease (0.14 cases per 100,000 population), resulting in an estimated 65 deaths (0.02 deaths per 100,000 population) [6]. Incidence of meningococcal disease in the United States varies according to age, with infants younger than one year of age being at the greatest risk, followed by persons 16 through 21 years of age [7] and [8]. The financial burden imposed by IMD on the healthcare system in the United States is substantial, as documented by a population-based observational study that reported the cost per hospitalization due to meningococcal meningitis as having risen from $18,417 in 1997 to $55,251 in 2010 [9]. The public health impact and economic burden of meningococcal infection underscore the need for effective vaccines and their optimal use.

Two quadrivalent (ACWY) conjugate vaccines (one conjugated to diphtheria toxoid and the other to a non-toxic mutant of diphtheria toxin [CRM197]), one quadrivalent (ACWY) polysaccharide vaccine, one bivalent (CY) conjugate vaccine, and two serogroup B vaccines are currently available for use in the United States for active immunization against meningococcal disease in various age groups [7] and [10]. Conjugate vaccines are effective across a wide age range, including children younger than 2 years of age, and offer an advantage over unconjugated polysaccharide vaccines in that they elicit T-cell–dependent responses characterized by the generation of memory B cells that drive booster antibody responses to exposure or to subsequent doses of conjugate vaccine [11]. Moreover, unlike unconjugated vaccines, they do not induce immunologic hyporesponsiveness, a phenomenon marked by an attenuated antibody response to subsequent antigenic exposure that results from the depletion of the memory B-cell pool [11]. A recent comparison of the population structure of invasive N. meningitidis in the United States before (2000–2005) and after (2006–2010) the introduction of conjugate vaccines has revealed substantial differences in the serogroup distribution between the two periods; however, vaccine-driven serogroup replacement was not evident [12].

Quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D), which is currently registered in more than 50 countries, was first licensed in the United States in 2005 for active immunization against IMD in adolescents and adults 11 through 55 years of age, in 2007 for use in children two through 10 years of age, and in 2011 for use in infants and toddlers nine through 23 months of age [7]. Although protective levels of antibodies have been documented up to three years following primary vaccination of adolescents with MenACWY-D [13], diminished vaccine effectiveness against C and Y disease in the United States has been described. This has been attributed to declining serum bactericidal assay (SBA) antibody titers over time, which have been observed in children first vaccinated at 2 years of age and in adolescents [7], [13], [14], [15], [16] and [17]. In 2010, the Advisory Committee on Immunization Practices (ACIP) in the United States recommended that a booster dose of MenACWY be administered at age 16 years if the primary dose had been administered at age 11 or 12 years, or at age 16 through 18 years if the primary dose had been administered at age 13 through 15 years [18]. In light of these recommendations, we conducted study MTA77, a phase 2, open-label study to determine the safety and immunogenicity of a single booster dose of MenACWY-D in persons who had received their first dose 4–6 years previously.

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