Antibody-Based Correlates of Protection against Cholera: Analysis of a Challenge Study of a Cholera-Naive Population

ABSTRACTImmunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (W. H. Chen et al., Clin Infect Dis 62:1329–1335, 2016,https://doi.org/10.1093/cid/ciw145), 134 North American cholera-naive volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD (Center for Vaccine Development) 103-HgR or placebo, and the titers of vibriocidal antibodies against the classical Inaba strain were assessed at 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulentVibrio choleraeO1 El Tor Inaba. Data from this trial suggest that the vaccine-induced increase in the vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with postvaccination vibriocidal antibody titers of ≥2,560 were protected against moderate/severe diarrhea, and 60/62 vaccinees who seroconverted or experienced a 4-fold or greater increase in vibriocidal antibody titer relative to prevaccination levels were similarly protected. Atypically high vibriocidal antibody titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same postvaccination titers. Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection. Thus, vibriocidal antibody seroconversion was found to be better than the vibriocidal antibody titer for inferring vaccine efficacy in cholera-naive populations for which studies based upon exposure toV. choleraeare impractical. (This study has been registered at ClinicalTrials.gov under registration no. NCT01895855.)

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Quest for Correlates of Protection against Tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00721-14 ◽

2015 ◽

Vol 22 (3) ◽

pp. 258-266 ◽

Cited By ~ 76

Author(s):

Kamlesh Bhatt ◽

Sheetal Verma ◽

Jerrold J. Ellner ◽

Padmini Salgame

Keyword(s):

T Cells ◽

Vaccine Development ◽

Interleukin 2 ◽

T Cell Response ◽

Content Type ◽

Alternative Pathways ◽

Correlates Of Protection ◽

Human Immune Response ◽

Ifn Γ ◽

High Level

ABSTRACTA major impediment to tuberculosis (TB) vaccine development is the lack of reliable correlates of immune protection or biomarkers that would predict vaccine efficacy. Gamma interferon (IFN-γ) produced by CD4+T cells and, recently, multifunctional CD4+T cells secreting IFN-γ, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance againstMycobacterium tuberculosisinfection is independent of IFN-γ and TNF secretion from CD4+T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4+T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediateM. tuberculosiscontrol and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response toM. tuberculosisto identify the correlates of protection in vaccination.

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The Combinations Chitosan-Pam3CSK4 and Chitosan-Monophosphoryl Lipid A: Promising Immune-Enhancing Adjuvants for Anticaries Vaccine PAc

Infection and Immunity ◽

10.1128/iai.00651-19 ◽

2019 ◽

Vol 87 (12) ◽

Author(s):

Yongli Bi ◽

Qingan Xu ◽

Lingkai Su ◽

Jiantao Xu ◽

Zhongfang Liu ◽

...

Keyword(s):

Lipid A ◽

Vaccine Development ◽

Protection Effect ◽

Content Type ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Tooth Surfaces ◽

Antibody Titers

ABSTRACT We previously demonstrated that recombinant protein PAc could be administered as an anticaries vaccine. However, the relatively weak immunogenicity of PAc limits its application. In the present study, we investigated the effect of two adjuvant combinations of chitosan plus Pam3CSK4 (chitosan-Pam3CSK4) and of chitosan plus monophosphoryl lipid A (chitosan-MPL) in the immune responses to the PAc protein in vivo and in vitro. PAc-chitosan-Pam3CSK4 or PAc-chitosan-MPL promoted significantly higher PAc-specific antibody titers in serum and saliva, inhibited Streptococcus mutans colonization onto the tooth surfaces, and endowed better protection effect with significantly less caries activities than PAc alone. Chitosan-Pam3CSK4 and chitosan-MPL showed no statistically significant differences. In conclusion, our study demonstrated that the chitosan-Pam3CSK4 and chitosan-MPL combinations are promising for anticaries vaccine development.

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Distinguishing Causation from Correlation in the Use of Correlates of Protection to Evaluate and Develop Influenza Vaccines

American Journal of Epidemiology ◽

10.1093/aje/kwz227 ◽

2019 ◽

Vol 189 (3) ◽

pp. 185-192 ◽

Cited By ~ 1

Author(s):

Wey Wen Lim ◽

Nancy H L Leung ◽

Sheena G Sullivan ◽

Eric J Tchetgen Tchetgen ◽

Benjamin J Cowling

Keyword(s):

Vaccine Efficacy ◽

Vaccine Development ◽

Influenza Vaccines ◽

Protective Effects ◽

Immune Markers ◽

Immune Marker ◽

Correlates Of Protection ◽

Rational Vaccine Design ◽

Individual Protection ◽

Protection Against Infection

Abstract There is increasing attention to the need to identify new immune markers for the evaluation of existing and new influenza vaccines. Immune markers that could predict individual protection against infection and disease, commonly called correlates of protection (CoPs), play an important role in vaccine development and licensing. Here, we discuss the epidemiologic considerations when evaluating immune markers as potential CoPs for influenza vaccines and emphasize the distinction between correlation and causation. While an immune marker that correlates well with protection from infection can be used as a predictor of vaccine efficacy, it should be distinguished from an immune marker that plays a mechanistic role in conferring protection against a clinical endpoint—the latter might be a more reliable predictor of vaccine efficacy and a more appropriate target for rational vaccine design. To clearly distinguish mechanistic and nonmechanistic CoPs, we suggest using the term “correlates of protection” for nonmechanistic CoPs, and ‘‘mediators of protection’’ for mechanistic CoPs. Furthermore, because the interactions among and relative importance of correlates or mediators of protection can vary according to age or prior vaccine experience, the effect sizes and thresholds for protective effects for CoPs could also vary in different segments of the population.

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Role of Opsonophagocytosis in Immune Protection against Malaria

Vaccines ◽

10.3390/vaccines8020264 ◽

2020 ◽

Vol 8 (2) ◽

pp. 264

Author(s):

Wolfgang W. Leitner ◽

Megan Haraway ◽

Tony Pierson ◽

Elke S. Bergmann-Leitner

Keyword(s):

Protective Immunity ◽

Defense Mechanisms ◽

Vaccine Development ◽

Immune Defense ◽

Complement Components ◽

Correlates Of Protection ◽

Immune Correlates ◽

Antibody Titers ◽

Simple Measurement ◽

Humoral Responses

The quest for immune correlates of protection continues to slow vaccine development. To date, only vaccine-induced antibodies have been confirmed as direct immune correlates of protection against a plethora of pathogens. Vaccine immunologists, however, have learned through extensive characterizations of humoral responses that the quantitative assessment of antibody responses alone often fails to correlate with protective immunity or vaccine efficacy. Despite these limitations, the simple measurement of post-vaccination antibody titers remains the most widely used approaches for vaccine evaluation. Developing and performing functional assays to assess the biological activity of pathogen-specific responses continues to gain momentum; integrating serological assessments with functional data will ultimately result in the identification of mechanisms that contribute to protective immunity and will guide vaccine development. One of these functional readouts is phagocytosis of antigenic material tagged by immune molecules such as antibodies and/or complement components. This review summarizes our current understanding of how phagocytosis contributes to immune defense against pathogens, the pathways involved, and defense mechanisms that pathogens have evolved to deal with the threat of phagocytic removal and destruction of pathogens.

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Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

Clinical and Vaccine Immunology ◽

10.1128/cvi.00301-15 ◽

2015 ◽

Vol 22 (10) ◽

pp. 1096-1108 ◽

Cited By ~ 10

Author(s):

Sherry L. Kurtz ◽

Karen L. Elkins

Keyword(s):

Mycobacterium Tuberculosis ◽

Vaccine Development ◽

Expression Profiles ◽

Adaptive Immune Response ◽

Peripheral Blood Lymphocytes ◽

Host Responses ◽

Content Type ◽

Correlates Of Protection ◽

Gene And Protein Expression

ABSTRACTA critical hindrance to the development of a novel vaccine againstMycobacterium tuberculosisis a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-basedin vitromodel system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strainMycobacterium bovisBCG or virulentM. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulentM. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses.

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Mechanistic Modeling of Mycobacterium tuberculosis Infection in Murine Models for Drug and Vaccine Efficacy Studies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01727-19 ◽

2020 ◽

Vol 64 (3) ◽

Author(s):

Nan Zhang ◽

Natasha Strydom ◽

Sandeep Tyagi ◽

Heena Soni ◽

Rokeya Tasneen ◽

...

Keyword(s):

Immune Response ◽

Mycobacterium Tuberculosis ◽

Vaccine Efficacy ◽

Vaccine Development ◽

Bacterial Load ◽

Mechanistic Modeling ◽

Response Dynamics ◽

Content Type ◽

Immune Effect ◽

Adaptive Immune

ABSTRACT Tuberculosis (TB) drug, regimen, and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics is essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection over time in BALB/c and athymic nude mice, which consisted of bacterial replication, bacterial death, and adaptive immune effects. The adaptive immune effect was best described by a sigmoidal function on both bacterial load and incubation time. Applications to demonstrate the utility of this baseline model showed (i) the important influence of the adaptive immune response on pyrazinamide (PZA) drug efficacy, (ii) a persistent adaptive immune effect in mice relapsing after chemotherapy cessation, and (iii) the protective effect of vaccines after M. tuberculosis challenge. These findings demonstrate the utility of our model for describing M. tuberculosis infection and corresponding adaptive immune dynamics for evaluating the efficacy of TB drugs, regimens, and vaccines.

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Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

Infection and Immunity ◽

10.1128/iai.00145-16 ◽

2016 ◽

Vol 84 (8) ◽

pp. 2175-2184 ◽

Cited By ~ 25

Author(s):

Danika L. Hill ◽

Danny W. Wilson ◽

Natalia G. Sampaio ◽

Emily M. Eriksson ◽

Victoria Ryg-Cornejo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Vaccine Development ◽

Field Isolate ◽

Field Studies ◽

Content Type ◽

Merozoite Antigens ◽

Transgenic Parasites ◽

Highly Correlated ◽

Immunological Assays ◽

Parasite Strains

It is unclear whether naturally acquired immunity toPlasmodium falciparumresults from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, orP. falciparumMSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.

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Activities of Murine Peripheral Blood Lymphocytes Provide Immune Correlates That Predict Francisella tularensis Vaccine Efficacy

Infection and Immunity ◽

10.1128/iai.01348-15 ◽

2016 ◽

Vol 84 (4) ◽

pp. 1054-1061 ◽

Cited By ~ 10

Author(s):

Roberto De Pascalis ◽

Lara Mittereder ◽

Nikki J. Kennett ◽

Karen L. Elkins

Keyword(s):

Gene Expression ◽

Immune Responses ◽

Francisella Tularensis ◽

Peripheral Blood ◽

Vaccine Efficacy ◽

Murine Splenocytes ◽

Content Type ◽

Correlates Of Protection ◽

Immune Correlates

We previously identified potential correlates of vaccine-induced protection againstFrancisella tularensisusing murine splenocytes and further demonstrated that the relative levels of gene expression varied significantly between tissues. In contrast to splenocytes, peripheral blood leukocytes (PBLs) represent a means to bridge vaccine efficacy in animal models to that in humans. Here we take advantage of this easily accessible source of immune cells to investigate cell-mediated immune responses against tularemia, whose sporadic incidence makes clinical trials of vaccines difficult. Using PBLs from mice vaccinated withF. tularensisLive Vaccine Strain (LVS) and related attenuated strains, we combined the control ofin vitroFrancisellareplication within macrophages with gene expression analyses. Thein vitrofunctions of PBLs, particularly the control of intramacrophage LVS replication, reflected the hierarchy ofin vivoprotection conferred by LVS-derived vaccines. Moreover, several genes previously identified by the evaluation of splenocytes were also found to be differentially expressed in immune PBLs. In addition, more extensive screening identified additional potential correlates of protection. Finally, expression of selected genes in mouse PBLs obtained shortly after vaccination, withoutex vivorestimulation, was different among vaccine groups, suggesting a potential tool to monitor efficacious vaccine-induced immune responses againstF. tularensis. Our studies demonstrate that murine PBLs can be used productively to identify potential correlates of protection againstF. tularensisand to expand and refine a comprehensive set of protective correlates.

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Neutralizing Anti-Heat-Stable Toxin (STa) Antibodies Derived from Enterotoxigenic Escherichia coli Toxoid Fusions with STa Proteins Containing N12S, L9A/N12S, or N12S/A14T Mutations Show Little Cross-Reactivity with Guanylin or Uroguanylin

Applied and Environmental Microbiology ◽

10.1128/aem.01737-17 ◽

2017 ◽

Vol 84 (2) ◽

Cited By ~ 4

Author(s):

Qiangde Duan ◽

Jiachen Huang ◽

Nan Xiao ◽

Hyesuk Seo ◽

Weiping Zhang

Keyword(s):

Escherichia Coli ◽

Epithelial Cells ◽

Vaccine Development ◽

Cross Reactivity ◽

Enterotoxigenic Escherichia Coli ◽

Content Type ◽

Renal Epithelial Cells ◽

Severe Diarrhea ◽

Heat Stable

ABSTRACT Heat-stable toxin (STa)-producing enterotoxigenic Escherichia coli (ETEC) strains are a top cause of moderate-to-severe diarrhea in children from developing countries and a common cause of travelers' diarrhea. Recent progress in using STa toxoids and toxoid fusions to induce neutralizing anti-STa antibodies has accelerated ETEC vaccine development. However, concern remains regarding whether the derived anti-STa antibodies cross-react with STa-like guanylin and uroguanylin, two guanylate cyclase C (GC-C) ligands regulating fluid and electrolyte transportation in human intestinal and renal epithelial cells. To further divert STa from guanylin and uroguanylin structurally and antigenically and to eliminate anti-STa antibody cross-reactivity with guanylin and uroguanylin, we mutated STa at the 9th (leucine), 12th (asparagine), and 14th (alanine) residues for the double and triple mutants STaL9A/N12S, STaL9A/A14H, STaN12S/A14T, and STaL9A/N12S/A14H. We then fused each STa mutant (three copies) to a monomeric heat-labile toxin (LT) mutant (mnLTR192G/L211A) for the toxoid fusions 3×STaL9A/N12S-mnLTR192G/L211A, 3×STaL9A/A14H-mnLTR192G/L211A, 3×STaN12S/A14T-mnLTR192G/L211A, and 3×STaL9A/N12S/A14H-mnLTR192G/L211A; examined each fusion for anti-STa immunogenicity; and assessed the derived antibodies for in vitro neutralization activity against STa toxicity and for cross-reactivity with guanylin and uroguanylin. Mice subcutaneously immunized with each fusion protein developed anti-STa antibodies, and the antibodies derived from 3×STaN12S-mnLTR192G/L211A, 3×STaL9A/N12S-mnLTR192G/L211A, or 3×STaN12S/A14T-mnLTR192G/L211A prevented STa from the stimulation of intracellular cGMP in T-84 cells. Competitive enzyme-linked immunosorbent assays (ELISAs) showed that guanylin and uroguanylin hardly blocked the binding of anti-STa antibodies to the coated STa-ovalbumin conjugate. These results indicated that antibodies derived from 3×STaN12S-mnLTR192G/L211A, 3×STaL9A/N12S-mnLTR192G/L211A, or 3×STaN12S/A14T-mnLTR192G/L211A neutralized STa and had little cross-reactivity with guanylin and uroguanylin, suggesting that these toxoid fusions are suitable antigens for ETEC vaccines. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) strains are a leading cause of children's diarrhea and travelers' diarrhea. Currently, there is no licensed vaccine against ETEC diarrhea. One key challenge is to identify safe antigens to induce antibodies neutralizing the key STa without cross-reacting with guanylin and uroguanylin, two important ligands controlling homeostasis in human intestinal and renal epithelial cells. In this study, we generated nontoxic fusion antigens that induced antibodies that neutralize STa enterotoxicity in vitro and do not cross-react with guanylin or uroguanylin. These fusions have become the preferred antigens for the development of ETEC vaccines to potentially prevent the deaths of hundreds of thousands of young children and hundreds of millions of diarrheal cases each year.

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292 The effect of pharmacological zinc on oral Salmonella vaccine efficacy

Journal of Animal Science ◽

10.1093/jas/skaa054.183 ◽

2020 ◽

Vol 98 (Supplement_3) ◽

pp. 108-108

Author(s):

Carson M DeMille ◽

Eric R Burrough ◽

Nicholas Gabler

Keyword(s):

Lymph Nodes ◽

Vaccine Efficacy ◽

Febrile Response ◽

Fecal Shedding ◽

Nursery Pigs ◽

Challenge Study ◽

Antibody Titers ◽

Pig Performance ◽

Culture Positive ◽

Improve Health

Abstract Pharmacological zinc (2,000-3,000 ppm) is commonly fed to nursery pigs to improve health and growth due to its antimicrobial and anti-inflammatory properties. The objective was to test if pharmacological zinc at time of oral Salmonella vaccination impeded vaccine efficacy. Sixty-four weaned pigs (5.1±0.7 kg BW) were used in a 2 x 2 factorial design. The diets were control (CON) or zinc (3,000 ppm for 1 week, 2,000 ppm for 2 weeks, and no additional zinc for 1 week [ZN]). On d 2 pigs were orally vaccinated for Salmonella with 1 of 2 commercially available vaccines, resulting in 4 treatments (CON1, CON2, ZN1, ZN2; n = 16/treatment). On d 28, n = 8 pigs/treatment were randomly selected and enrolled in a S. Typhimurium challenge study. On d 35 post-weaned, all pigs were inoculated with 108 cfu of a field S. Typhimurium isolate. Pig performance, febrile response, fecal shedding and serology was assessed over a 7-d challenge period. On dpi 7 all pigs were euthanized, and colon contents and ileocecal lymph nodes were collected for culture. The effect of nursery diet, vaccine and their interaction was assessed. Pigs were confirmed Salmonella culture positive at dpi 2 and 6 pigs were culture positive from the ileocecal lymph nodes at dpi 7. Salmonella-specific antibody titers (S/P) increased (P < 0.001) from dpi 0 (0.31) to 7 (2.01), and a time-by-vaccine interaction was reported (P < 0.05). Irrespective of diet and vaccine, core temperatures increased from 39.5°C (dpi 0) to 39.7°C (dpi 2) before decreasing (P = 0.02). Over the challenge period, ADG did not differ (0.67, 0.64, 0.61, 0.62 kg/d, CON1, CON2, ZN1, ZN2, respectively, P = 0.654). Furthermore, ADFI and G:F did not differ by diet or vaccine (P >0.05). In conclusion, pharmacological Zn did not inhibit efficacy of oral Salmonella vaccines.

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