scholarly journals Preliminary Evaluation of the Safety and Immunogenicity of an Antimalarial Vaccine Candidate Modified Peptide (IMPIPS) Mixture in a Murine Model

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Jennifer Lambraño ◽  
Hernando Curtidor ◽  
Catalina Avendaño ◽  
Diana Díaz-Arévalo ◽  
Leonardo Roa ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Effective Vaccine ◽  
Preliminary Evaluation ◽  
Repeat Dose ◽  
Primate Model ◽  
Humoral Immune ◽  
Native Proteins ◽  
Modified Peptides ◽  
Local Safety

Malaria continues being a high-impact disease regarding public health worldwide; the WHO report for malaria in 2018 estimated that ~219 million cases occurred in 2017, mostly caused by the parasite Plasmodium falciparum. The disease cost the lives of more than 400,000 people, mainly in Africa. In spite of great efforts aimed at developing better prevention (i.e., a highly effective vaccine), diagnosis, and treatment methods for malaria, no efficient solution to this disease has been advanced to date. The Fundación Instituto de Inmunología de Colombia (FIDIC) has been developing studies aimed at furthering the search for vaccine candidates for controlling P. falciparum malaria. However, vaccine development involves safety and immunogenicity studies regarding their formulation in animal models before proceeding to clinical studies. The present work has thus been aimed at evaluating the safety and immunogenicity of a mixture of 23 chemically synthesised, modified peptides (immune protection-inducing protein structure (IMPIPS)) derived from different P. falciparum proteins. Single and repeat dose assays were thus used with male and female BALB/c mice which were immunised with the IMPIPS mixture. It was found that single and repeat dose immunisation with the IMPIPS mixture was safe, both locally and systemically. It was observed that the antibodies so stimulated recognised the parasite’s native proteins and inhibited merozoite invasion of red blood cells in vitro when evaluating the humoral immune response induced by the IMPIPS mixture. Such results suggested that the IMPIPS peptide mixture could be a safe candidate to be tested during the next stage involved in developing an antimalarial vaccine, evaluating local safety, immunogenicity, and protection in a nonhuman primate model.

scholarly journals A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1408
Author(s):  
Qiao Li ◽  
Zhihua Liu ◽  
Yi Liu ◽  
Chen Liang ◽  
Jiayi Shu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Development ◽  
Inbred Mouse ◽  
Effective Vaccine ◽  
Mouse Strains ◽  
Cellular Immune Responses ◽  
Recombinant Hbsag ◽  
Cellular Immune

TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future.

scholarly journals Resolution ofStaphylococcus aureusBiofilm Infection Using Vaccination and Antibiotic Treatment

2011 ◽  
Vol 79 (4) ◽  
pp. 1797-1803 ◽  
Author(s):  
Rebecca A. Brady ◽  
Graeme A. O'May ◽  
Jeff G. Leid ◽  
Megan L. Prior ◽  
J. William Costerton ◽  
...  
Keyword(s):  
Antibiotic Treatment ◽  
Vaccine Development ◽  
Hypothetical Protein ◽  
Quadrivalent Vaccine ◽  
Effective Vaccine ◽  
Vast Number ◽  
Protective Antigens ◽  
Biofilm Model

ABSTRACTStaphylococcus aureusinfections, particularly those from methicillin-resistant strains (i.e., MRSA), are reaching epidemic proportions, with no effective vaccine available. The vast number and transient expression of virulence factors in the infectious course of this pathogen have made the discovery of protective antigens particularly difficult. In addition, the divergent planktonic and biofilm modes of growth with their accompanying proteomic changes also demonstrate significant hindrances to vaccine development. In this study, a multicomponent vaccine was evaluated for its ability to clear a staphylococcal biofilm infection. Antigens (glucosaminidase, an ABC transporter lipoprotein, a conserved hypothetical protein, and a conserved lipoprotein) were chosen since they were found in previous studies to have upregulated and sustained expression in a biofilm, bothin vitroandin vivo. Antibodies against these antigens were first used in microscopy studies to localize their expression inin vitrobiofilms. Each of the four antigens showed heterogeneous production in various locations within the complex biofilm community in the biofilm. Based upon these studies, the four antigens were delivered simultaneously as a quadrivalent vaccine in order to compensate for this varied production. In addition, antibiotic treatment was also administered to clear the remaining nonattached planktonic cells since the vaccine antigens may have been biofilm specific. The results demonstrated that when vaccination was coupled with vancomycin treatment in a biofilm model of chronic osteomyelitis in rabbits, clinical and radiographic signs of infection significantly reduced by 67 and 82%, respectively, compared to infected animals that were either treated with vancomycin or left untreated. In contrast, vaccination alone resulted in a modest, and nonsignificant, decrease in clinical (34% reduction) and radiographic signs (9% reduction) of infection, compared to nonvaccinated animal groups untreated or treated with vancomycin. Lastly, MRSA biofilm infections were significantly cleared in 87.5% of vaccinated and antibiotic-treated animals, while antibiotics or vaccine alone could not significantly clear infection compared to controls (55.6, 22.2, and 33.3% clearance rates, respectively). This approach to vaccine development may lead to the generation of vaccines against other pathogenic biofilm bacteria.

scholarly journals Theileria equi claudin like apicomplexan microneme protein contains neutralization-sensitive epitopes and interacts with components of the equine erythrocyte membrane skeleton

2021 ◽  
Author(s):  
Cynthia Onzere ◽  
Lindsay Fry ◽  
Richard Bishop ◽  
Marta Silva ◽  
Reginaldo Bastos ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Vaccine Development ◽  
Membrane Skeleton ◽  
Host Cells ◽  
Effective Vaccine ◽  
Theileria Equi ◽  
Anion Exchange Protein ◽  
Microneme Protein

Abstract Theileria equi (T. equi) is a widely distributed apicomplexan parasite that causes severe hemolytic anemia in equid species. There is currently no effective vaccine for control of the parasite and understanding the mechanism that T. equi utilizes to invade host cells may be crucial for vaccine development. Unlike most apicomplexan species studied to date, the role of micronemes in T. equi invasion of host cells is unknown. We therefore assessed the role of the T. equi claudin-like apicomplexan microneme protein (CLAMP) in the invasion of equine erythrocytes as a first step towards understanding the role of this organelle in the parasite. Our findings show that CLAMP is expressed in the merozoite and intra-erythrocytic developmental stages of T. equi and in vitro neutralization experiments suggest that the protein is involved in erythrocyte invasion. Proteomic analyses indicate that CLAMP interacts with the equine erythrocyte α-and β- spectrin chains in the initial stages of T. equi invasion and maintains these interactions while also associating with the anion-exchange protein, tropomyosin 3, band 4.1 and cytoplasmic actin 1 after invasion. Additionally, serological analyses show that T. equi-infected horses mount robust antibody responses against CLAMP indicating that the protein is immunogenic and therefore represents a potential vaccine candidate.

scholarly journals Using Plasmodium knowlesi as a model for screening Plasmodium vivax blood-stage malaria vaccine targets reveals new candidates

2021 ◽  
Vol 17 (7) ◽  
pp. e1008864
Author(s):  
Duncan N. Ndegwa ◽  
Prasun Kundu ◽  
Jessica B. Hostetler ◽  
Alejandro Marin-Menendez ◽  
Theo Sanderson ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Culture System ◽  
Vaccine Development ◽  
Expression System ◽  
Critical Role ◽  
Blood Stage ◽  
Effective Vaccine ◽  
Mammalian Expression ◽  
Close Phylogenetic Relationship

Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum, the P. vivax life-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine against P. vivax blood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development in P. vivax, however, lags considerably behind P. falciparum, which has many identified targets with several having transitioned to Phase II testing. By contrast only one P. vivax blood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuous in vitro culture system for P. vivax limits systematic screening of new candidates. We used the close phylogenetic relationship between P. vivax and P. knowlesi, for which an in vitro culture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritise P. vivax blood-stage targets. A panel of P. vivax proteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins in P. knowlesi. These antibodies were then tested for inhibition of growth and invasion of both wild type P. knowlesi and chimeric P. knowlesi lines modified using CRISPR/Cas9 to exchange P. knowlesi genes with their P. vivax orthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility of P. knowlesi as a model for P. vivax vaccine development and prioritizing antigens for further follow up.

Enhanced Thymopoiesis as an Alternative Therapeutic Option for COVID-19

2021 ◽  
Vol 7 (2) ◽  
Author(s):  
Genebat M ◽  
◽  
Calderón A ◽  
Tarancón-Díez L ◽  
Muñoz-Fernández MA ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Vaccine Development ◽  
Alternative Hypothesis ◽  
Therapeutic Option ◽  
Multiorgan Failure ◽  
Effective Vaccine ◽  
Elderly Subjects ◽  
Cellular Mechanisms ◽  
Relevant Role

The pandemic caused by SARS-CoV-2 infection (COVID-19 disease) has expanded worldwide. Currently, it is well known that advanced age is an independent predictor of mortality and severe clinical outcome, apart from other comorbidities [1]. Underlying molecular and cellular mechanisms that could explain the severe clinical outcome among elderly subjects are not well known [2], although it has been described that both immunosenescence and a low-level systemic inflammation (inflamm-aging) could also play a relevant role [3,4]. Now a days, apart from an effective vaccine development, research efforts are focused on therapeutic approaches that could minimize both the viral replication and the further inflammatory cascade driving to respiratory distress and multiorgan failure; however, up to now, no specific therapy for SARS-CoV-2 infection has been established [5]. Awaiting for definitive and conclusive results from prospective clinical trials, antiviral and immunomodulatory drugs currently employed in SARS-CoV-2-infected subjects are based on their biological plausibility according to the mechanism of action or in vitro efficacy, but not in a definitive scientific evidences. Taken altogether, alternative hypothesis about underlying mechanisms driving to an impaired clinical outcome in COVID-19 disease are required. In this sense, even the universally accepted role of the cytokine storm has been questioned [6]. Hence, the greater hypothesis is considered the greater and more beneficial therapeutic options could be tested. Recently, our group has suggested that thymic dysfunction could play a relevant role in the impaired clinical outcome observed in elderly SARS-CoV-2-infected subjects [7]. Thus, the main objective of the present opinion paper is to explore a new therapeutic option for COVID-19 disease, based on enhancing thymic function.

scholarly journals Going beyond clinical routine in SARS-CoV-2 antibody testing - A multiplex corona virus antibody test for the evaluation of cross-reactivity to endemic coronavirus antigens

2020 ◽  
Author(s):  
Matthias Becker ◽  
Monika Strengert ◽  
Daniel Junker ◽  
Tobias Kerrinnes ◽  
Philipp D. Kaiser ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Antibody Test ◽  
Cross Reactivity ◽  
Antibody Testing ◽  
N Protein ◽  
Humoral Immune ◽  
In Vitro Diagnostic ◽  
Human Coronaviruses ◽  
Multiplexed Immunoassay

Given the importance of the humoral immune response to SARS-CoV-2 as a global benchmark for immunity, a detailed analysis is needed to (i) monitor seroconversion in the general population, (ii) understand manifestation and progression of the disease, and (iii) predict the outcome of vaccine development. Currently available serological assays utilize single analyte technologies such as ELISA to measure antibodies against SARS-CoV-2 antigens including spike (S) or nucleocapsid (N) protein. To measure individual antibody (IgG and IgA) responses against SARS-CoV-2 and the endemic human coronaviruses (hCoVs) NL63, 229E, OC43, and HKU1, we developed a multiplexed immunoassay (CoVi-plex), for which we included S and N proteins of these coronaviruses in an expanded antigen panel. Compared to commercial in vitro diagnostic (IVD) tests our CoVi-plex achieved the highest sensitivity and specificity when analyzing 310 SARS-CoV-2 infected and 866 uninfected individuals. Simultaneously we see high IgG responses against hCoVs throughout all samples, whereas no consistent cross reactive IgG response patterns can be defined. In summary, our CoVi-plex is highly suited to monitor vaccination studies and will facilitate epidemiologic screenings for the humoral immunity toward pandemic as well as endemic coronaviruses.

scholarly journals Multistage Multiantigen Heterologous Prime Boost Vaccine forPlasmodium knowlesi Malaria Provides Partial Protection in Rhesus Macaques

2001 ◽  
Vol 69 (9) ◽  
pp. 5565-5572 ◽  
Author(s):  
William O. Rogers ◽  
J. Kevin Baird ◽  
Anita Kumar ◽  
John A. Tine ◽  
Walter Weiss ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Vaccine Development ◽  
Plasmodium Knowlesi ◽  
Rhesus Macaques ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Antibody Responses ◽  
Primate Model ◽  
Boost Vaccine

ABSTRACT A nonhuman primate model for malaria vaccine development allowing reliable, stringent sporozoite challenge and evaluation of both cellular and antibody responses is needed. We therefore constructed a multicomponent, multistage DNA vaccine for the simian malaria species Plasmodium knowlesi including two preerythrocytic-stage antigens, the circumsporozoite protein (PkCSP) and sporozoite surface protein 2 (PkSSP2), and two blood stage antigens, apical merozoite antigen 1 (PkAMA1) and merozoite surface protein 1 (PkMSP1p42), as well as recombinant canarypox viruses encoding the four antigens (ALVAC-4). The DNA vaccine plasmids expressed the corresponding antigens in vitro and induced antiparasite antibodies in mice. Groups of four rhesus monkeys received three doses of a mixture of the four DNA vaccine plasmids and a plasmid encoding rhesus granulocyte-monocyte colony-stimulating factor, followed by boosting with a single dose of ALVAC-4. Three groups received the priming DNA doses by different routes, either by intramuscular needle injection, by intramuscular injection with a needleless injection device, the Biojector, or by a combination of intramuscular and intradermal routes by Biojector. Animals immunized by any route developed antibody responses against sporozoites and infected erythrocytes and against a recombinant PkCSP protein, as well as gamma interferon-secreting T-cell responses against peptides from PkCSP. Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys. This model will be important in preclinical vaccine development.

scholarly journals Assembly of Human Immunodeficiency Virus (HIV) Antigens on Bacteriophage T4: a Novel In Vitro Approach To Construct Multicomponent HIV Vaccines

2006 ◽  
Vol 80 (15) ◽  
pp. 7688-7698 ◽  
Author(s):  
Taheri Sathaliyawala ◽  
Mangala Rao ◽  
Danielle M. Maclean ◽  
Deborah L. Birx ◽  
Carl R. Alving ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Capsid Protein ◽  
Vaccine Development ◽  
Bacteriophage T4 ◽  
Th2 Response ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Phage T4 ◽  
Immunodeficiency Virus

ABSTRACT Bacteriophage T4 capsid is an elongated icosahedron decorated with 155 copies of Hoc, a nonessential highly antigenic outer capsid protein. One Hoc monomer is present in the center of each major capsid protein (gp23*) hexon. We describe an in vitro assembly system which allows display of HIV antigens, p24-gag, Nef, and an engineered gp41 C-peptide trimer, on phage T4 capsid surface through Hoc-capsid interactions. In-frame fusions were constructed by splicing the human immunodeficiency virus (HIV) genes to the 5′ or 3′ end of the Hoc gene. The Hoc fusion proteins were expressed, purified, and displayed on hoc − phage particles in a defined in vitro system. Single or multiple antigens were efficiently displayed, leading to saturation of all available capsid binding sites. The displayed p24 was highly immunogenic in mice in the absence of any external adjuvant, eliciting strong p24-specific antibodies, as well as Th1 and Th2 cellular responses with a bias toward the Th2 response. The phage T4 system offers new direction and insights for HIV vaccine development with the potential to increase the breadth of both cellular and humoral immune responses.

scholarly journals Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthias Becker ◽  
Monika Strengert ◽  
Daniel Junker ◽  
Philipp D. Kaiser ◽  
Tobias Kerrinnes ◽  
...  
Keyword(s):  
Immune Response ◽  
Vaccine Development ◽  
Cross Reactivity ◽  
Response Patterns ◽  
Nucleocapsid Proteins ◽  
Humoral Immune ◽  
In Vitro Diagnostic ◽  
Human Coronaviruses ◽  
Sample Set

AbstractThe humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.

scholarly journals Anticytomegalovirus Peptides Point to New Insights for CMV Entry Mechanisms and the Limitations ofIn VitroScreenings

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Joseph W. Jackson ◽  
Trevor J. Hancock ◽  
Pranay Dogra ◽  
Ravi Patel ◽  
Ravit Arav-Boger ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Vaccine Development ◽  
Murine Cytomegalovirus ◽  
Effective Vaccine ◽  
Antiviral Peptides ◽  
Highly Effective ◽  
Binding Peptides ◽  
Cell Spread

ABSTRACTHuman cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease followingin uteroexposure, during primary infection, or latent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation. These treatments have unwanted side effects, and HCMV is becoming resistant to them. Therefore, we sought to develop an alternative treatment that targets a different stage in viral infection. Currently, small antiviral peptides are being investigated as anti-influenza and anti-HIV treatments. We have developed heparan sulfate-binding peptides as tools for preventing CMV infections. These peptides are highly effective at stopping infection of fibroblasts within vitro-derived HCMV and murine cytomegalovirus (MCMV). However, they do not prevent MCMV infectionin vivo. Interestingly, these peptides inhibit infectivity ofin vivo-derived CMVs, albeit not as well as tissue culture-grown CMVs. We further demonstrate that this class of heparan sulfate-binding peptides is incapable of inhibiting MCMV cell-to-cell spread, which is independent of heparan sulfate usage. These data indicate that inhibition of CMV infection can be achieved using synthetic polybasic peptides, but cell-to-cell spread andin vivo-grown CMVs require further investigation to design appropriate anti-CMV peptides.IMPORTANCEIn the absence of an effective vaccine to prevent HCMV infections, alternative interventions must be developed. Prevention of viral entry into susceptible cells is an attractive alternative strategy. Here we report that heparan sulfate-binding peptides effectively inhibit entry into fibroblasts ofin vitro-derived CMVs and partially inhibitin vivo-derived CMVs. This includes the inhibition of urine-derived HCMV (uCMV), which is highly resistant to antibody neutralization. While these antiviral peptides are highly effective at inhibiting cell-free virus, they do not inhibit MCMV cell-to-cell spread. This underscores the need to understand the mechanism of cell-to-cell spread and differences betweenin vivo-derived versusin vitro-derived CMV entry to effectively prevent CMV’s spread.

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