The Novel Oral Typhoid Vaccine M01ZH09 Is Well Tolerated and Highly Immunogenic in 2 Vaccine Presentations

Kirkpatrick, Beth D.; Tenney, Katherine M.; Larsson, Catherine J.; O’Neill, J. Patrick; Ventrone, Cassandra H.; Bentley, M. G.; Upton, Anthony; Hindle, Zoë; Fidler, Christine; Kutzko, Deborah; Holdridge, Regan; Lapointe, C; Hamlet, Sandra; Chatfield, Steven N.

doi:10.1086/431605

Cited by 62 publications

(54 citation statements)

References 21 publications

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“…We suspected that S. Typhi-specific antibodies (IgG, IgA, and IgM at early time points) were the immune opsonins primarily responsible for the observed increases in phagocytosis of S. Typhi. Previous studies showed that all subjects tested in the opsonophagocytosis assays produced IgG and IgA specific to S. Typhi lipopolysaccharide (LPS) following vaccination with ZH9 (21,22,31). All serum samples used in the opsonophagocytosis assays were heat treated (56°C; 30 min) to inactivate the complement system and remove its contribution to phagocytic uptake.…”

Section: Postvaccination Opsonins Increase Uptake Of Wild-type Smentioning

confidence: 99%

“…However, both vaccines have drawbacks that necessitate the development of next-generation typhoid vaccines: Ty21a requires 3 or 4 oral doses, while Vi requires a needle injection, and refrigeration is necessary for both (13,14). Several next-generation vaccines, designed to optimize efficacy and simplify delivery, are currently in human trials, including a single-oral-dose typhoid vaccine, M01ZH09 (S. Typhi Ty2 ⌬aroC ⌬ssaV) (4,14,17,22,28,31,32,41).…”

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confidence: 99%

“…A better understanding of the function of antibodies mounted in response to disease or vaccination addresses major challenges in understanding humoral immune responses to typhoid disease and aids in the evaluation of new typhoid vaccines. This work capitalizes on clinical specimens following study of the candidate typhoid vaccine M01ZH09 (S. Typhi Ty2 ⌬aroC ⌬ssaV, here called ZH9), a single-oraldose live attenuated vaccine with two independently attenuating mutations in healthy American adults (21,22,31). We describe the functional role of opsonins generated following vaccination with ZH9 in the uptake and killing of wild-type S. Typhi.…”

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confidence: 99%

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Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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Although vaccines have been available for over a century, a correlate of protection for typhoid fever has yet to be identified. Antibodies are produced in response to typhoid infection and vaccination and are generally used as the gold standard for determining vaccine immunogenicity, even though their role in clearance of Salmonella enterica serovar Typhi infections is poorly defined. Here, we describe the first functional characterization of S. Typhi-specific antibodies following vaccination with a new vaccine, M01ZH09 (Ty2 ⌬aroC ⌬ssaV). We determined that postvaccination sera increased the uptake of wild-type S. Typhi by human macrophages up to 2.3-fold relative to prevaccination (day 0) or placebo samples. These results were recapitulated using immunoglobulins purified from postvaccination serum, demonstrating that antibodies were largely responsible for increases in uptake. Imaging verified that macrophages internalized 2-to 9.5-fold more S. Typhi when the bacteria were opsonized with postvaccination sera than when the bacteria were opsonized with day 0 or placebo sera. Once inside macrophages, the survival of S. Typhi was reduced as much as 50% when opsonized with postvaccination sera relative to day 0 or placebo serum samples. Lastly, bactericidal assays indicated that antibodies generated postvaccination were recognized by complement factors and assisted in killing S. Typhi: mean postvaccination bactericidal antibody titers were higher at all time points than placebo and day 0 titers. These data clearly demonstrate that there are at least two mechanisms by which antibodies facilitate killing of S. Typhi. Future work could lead to improved immunogenicity tests associated with vaccine efficacy and the identification of correlates of protection against typhoid fever.

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Section: Postvaccination Opsonins Increase Uptake Of Wild-type Smentioning

confidence: 99%

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Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

et al. 2011

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“…This alternative technique has been used to preserve many biological products such as bovine pericardium (9,11) , human red blood cells (12) , epidermal keratinocytes (13) , amniotic membrane (14) , vaccines (15) and others.…”

Section: Dehydrationmentioning

confidence: 99%

Freeze-drying as an alternative method of human sclera preservation

Frota¹,

Filho²,

Dias³

et al. 2008

Arq. Bras. Oftalmol.

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“…Most vaccine researchers avoid the problem low gastric pH poses by coating their vaccine in a protective enteric capsule (e.g., Ty21a) or by coadministration of an antacid (usually sodium bicarbonate) at the time of immunization (17)(18)(19)(20)(21)(22). Preventing vaccine exposure to low pH increases the number of viable cells that reach the intestine and improves vaccine immunogenicity (22,23).…”

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Low-pH Rescue of Acid-Sensitive Salmonella enterica Serovar Typhi Strains by a Rhamnose-Regulated Arginine Decarboxylase System

et al. 2013

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bFor Salmonella, transient exposure to gastric pH prepares invading bacteria for the stresses of host-cell interactions. To resist the effects of low pH, wild-type Salmonella enterica uses the acid tolerance response and the arginine decarboxylase acid resistance system. However, arginine decarboxylase is typically repressed under routine culture conditions, and for many live attenuated Salmonella vaccine strains, the acid tolerance response is unable to provide the necessary protection. The objective of this study was to enhance survival of Salmonella enterica serovar Typhi vaccine strains at pHs 3.0 and 2.5 to compensate for the defects in the acid tolerance response imposed by mutations in rpoS, phoPQ, and fur. We placed the arginine decarboxylase system (adiA and adiC) under the control of the P araBAD or P rhaBAD promoter to provide inducible acid resistance when cells are grown under routine culture conditions. The rhamnose-regulated promoter P rhaBAD was less sensitive to the presence of its cognate sugar than the arabinose-regulated promoter P araBAD and provided tighter control over adiA expression. Increased survival at low pH was only observed when adiA and adiC were coregulated by rhamnose and depended on the presence of rhamnose in the culture medium and arginine in the challenge medium. Rhamnose-regulated acid resistance significantly improved the survival of ⌬aroD and ⌬phoPQ mutants at pHs 3 and 2.5 but only modestly improved the survival of a fur mutant. The construction of the rhamnose-regulated arginine decarboxylase system allowed us to render S. Typhi acid resistant (to pH 2.5) on demand, with survival levels approximately equivalent to that of the native arginine decarboxylase system.

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The Novel Oral Typhoid Vaccine M01ZH09 Is Well Tolerated and Highly Immunogenic in 2 Vaccine Presentations

Abstract: The oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in a single oral dose, with and without prevaccination with a bicarbonate buffer. Field studies to demonstrate protective efficacy are planned.

Cited by 62 publications

References 21 publications

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi

Freeze-drying as an alternative method of human sclera preservation

Low-pH Rescue of Acid-Sensitive Salmonella enterica Serovar Typhi Strains by a Rhamnose-Regulated Arginine Decarboxylase System

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