The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples

Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

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New highly antigenic linear B cell epitope peptides from PvAMA-1 as potential vaccine candidates

PLoS ONE ◽

10.1371/journal.pone.0258637 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0258637

Author(s):

Raianna F. Fantin ◽

Vanessa G. Fraga ◽

Camila A. Lopes ◽

Isabella C. de Azevedo ◽

João L. Reis-Cunha ◽

...

Keyword(s):

Immune Response ◽

B Cell ◽

Structure Prediction ◽

Markov Models ◽

Vaccine Development ◽

Secondary Structure Prediction ◽

Cell Epitope ◽

B Cell Epitope ◽

Potential Vaccine ◽

Vaccine Approach

Peptide-based vaccines have demonstrated to be an important way to induce long-lived immune responses and, therefore, a promising strategy in the rational of vaccine development. As to malaria, among the classic vaccine targets, the Apical membrane antigen (AMA-1) was proven to have important B cell epitopes that can induce specific immune response and, hence, became key players for a vaccine approach. The peptides selection was carried out using a bioinformatic approach based on Hidden Markov Models profiles of known antigens and propensity scale methods based on hydrophilicity and secondary structure prediction. The antigenicity of the selected B-cell peptides was assessed by multiple serological assays using sera from acute P.vivax infected subjects. The synthetic peptides were recognized by 45.5%, 48.7% and 32.2% of infected subjects for peptides I, II and III respectively. Moreover, when synthetized together (tripeptide), the reactivity increases up to 62%, which is comparable to the reactivity found against the whole protein PvAMA-1 (57%). Furthermore, IgG reactivity against the tripeptide after depletion was reduced by 42%, indicating that these epitopes may be responsible for a considerable part of the protein immunogenicity. These results represent an excellent perspective regarding future chimeric vaccine constructions that may come to contemplate several targets with the potential to generate the robust and protective immune response that a vivax malaria vaccine needs to succeed.

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Sequence analysis of Plasmodium vivax Duffy binding proteins reveals the presence of unique haplotypes and diversifying selection in Ethiopian isolates

Malaria Journal ◽

10.1186/s12936-021-03843-7 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Lemu Golassa ◽

Alebachew Messele ◽

Eniyou Cheryll Oriero ◽

Alfred Amambua-Ngwa

Keyword(s):

Vaccine Development ◽

Haplotype Diversity ◽

Sri Lankan ◽

Duffy Binding Protein ◽

Synonymous Mutations ◽

South Korean ◽

Blood Stage Infection ◽

Vaccine Approach ◽

Papua New Guinean ◽

Reference Haplotype

Abstract Background Red blood cell invasion by the Plasmodium vivax merozoite requires interaction between the Duffy antigen receptor for chemokines (DARC) and the P. vivax Duffy-binding protein II (PvDBPII). Given that the disruption of this interaction prevents P. vivax blood-stage infection, a PvDBP-based vaccine development has been well recognized. However, the polymorphic nature of PvDBPII prevents a strain transcending immune response and complicates attempts to design a vaccine. Methods Twenty-three P. vivax clinical isolates collected from three areas of Ethiopia were sequenced at the pvdbpII locus. A total of 392 global pvdbpII sequences from seven P. vivax endemic countries were also retrieved from the NCBI archive for comparative analysis of genetic diversity, departure from neutrality, linkage disequilibrium, genetic differentiation, PvDBP polymorphisms, recombination and population structure of the parasite population. To establish a haplotype relationship a network was constructed using the median joining algorithm. Results A total of 110 variable sites were found, of which 44 were parsimony informative. For Ethiopian isolates there were 12 variable sites of which 10 were parsimony informative. These parsimony informative variants resulted in 10 nonsynonymous mutations. The overall haplotype diversity for global isolates was 0.9596; however, the haplotype diversity was 0.874 for Ethiopia. Fst values for genetic revealed Ethiopian isolates were closest to Indian isolates as well as to Sri Lankan and Sudanese isolates but further away from Mexican, Papua New Guinean and South Korean isolates. There was a total of 136 haplotypes from the 415 global isolates included for this study. Haplotype prevalence ranged from 36.76% to 0.7%, from this 74.2% were represented by single parasite isolates. None of the Ethiopian isolates grouped with the Sal I reference haplotype. From the total observed nonsynonymous mutations 13 mapped to experimentally verified epitope sequences. Including 10 non-synonymous mutations from Ethiopia. However, all the polymorphic regions in Ethiopian isolates were located away from DARC, responsible for junction formation. Conclusion The results of this study are concurrent with the multivalent vaccine approach to design an effective treatment. However, the presence of novel haplotypes in Ethiopian isolates that were not shared by other global sequences warrant further investigation.

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Flavivirus NS1 and Its Potential in Vaccine Development

Vaccines ◽

10.3390/vaccines9060622 ◽

2021 ◽

Vol 9 (6) ◽

pp. 622

Author(s):

Kassandra L. Carpio ◽

Alan D. T. Barrett

Keyword(s):

Vaccine Development ◽

Virus Assembly ◽

Ns1 Protein ◽

Human Pathogens ◽

Unusual Structure ◽

Replication Complex ◽

Virus Challenge ◽

Humoral Immune ◽

Tick Borne Encephalitis ◽

Flavivirus Infection

The Flavivirus genus contains many important human pathogens, including dengue, Japanese encephalitis (JE), tick-borne encephalitis (TBE), West Nile (WN), yellow fever (YF) and Zika (ZIK) viruses. While there are effective vaccines for a few flavivirus diseases (JE, TBE and YF), the majority do not have vaccines, including WN and ZIK. The flavivirus nonstructural 1 (NS1) protein has an unusual structure–function because it is glycosylated and forms different structures to facilitate different roles intracellularly and extracellularly, including roles in the replication complex, assisting in virus assembly, and complement antagonism. It also plays a role in protective immunity through antibody-mediated cellular cytotoxicity, and anti-NS1 antibodies elicit passive protection in animal models against a virus challenge. Historically, NS1 has been used as a diagnostic marker for the flavivirus infection due to its complement fixing properties and specificity. Its role in disease pathogenesis, and the strong humoral immune response resulting from infection, makes NS1 an excellent target for inclusion in candidate flavivirus vaccines.

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Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT – IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy)

Infectious Agents and Cancer ◽

10.1186/s13027-021-00375-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Ernesta Cavalcanti ◽

Maria Antonietta Isgrò ◽

Domenica Rea ◽

Lucia Di Capua ◽

Giusy Trillò ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Healthcare Workers ◽

Geometric Mean ◽

Vaccination Strategy ◽

Antibody Responses ◽

Cancer Center ◽

Serum Samples ◽

Humoral Immune ◽

History Of

Abstract Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects. Methods We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated. Results Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ($$ \overline{x} $$ x ¯ =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose. Conclusions The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.

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Experimental Morogoro Virus Infection in Its Natural Host, Mastomys natalensis

Viruses ◽

10.3390/v13050851 ◽

2021 ◽

Vol 13 (5) ◽

pp. 851

Author(s):

Chris Hoffmann ◽

Stephanie Wurr ◽

Elisa Pallasch ◽

Sabrina Bockholt ◽

Toni Rieger ◽

...

Keyword(s):

Persistent Infection ◽

Virus Transmission ◽

Host Population ◽

Natural Host ◽

Lassa Virus ◽

Mastomys Natalensis ◽

Natural Hosts ◽

History Of ◽

Morogoro Virus ◽

The Impact

Natural hosts of most arenaviruses are rodents. The human-pathogenic Lassa virus and several non-pathogenic arenaviruses such as Morogoro virus (MORV) share the same host species, namely Mastomys natalensis (M. natalensis). In this study, we investigated the history of infection and virus transmission within the natural host population. To this end, we infected M. natalensis at different ages with MORV and measured the health status of the animals, virus load in blood and organs, the development of virus-specific antibodies, and the ability of the infected individuals to transmit the virus. To explore the impact of the lack of evolutionary virus–host adaptation, experiments were also conducted with Mobala virus (MOBV), which does not share M. natalensis as a natural host. Animals infected with MORV up to two weeks after birth developed persistent infection, seroconverted and were able to transmit the virus horizontally. Animals older than two weeks at the time of infection rapidly cleared the virus. In contrast, MOBV-infected neonates neither developed persistent infection nor were able to transmit the virus. In conclusion, we demonstrate that MORV is able to develop persistent infection in its natural host, but only after inoculation shortly after birth. A related arenavirus that is not evolutionarily adapted to M. natalensis is not able to establish persistent infection. Persistently infected animals appear to be important to maintain virus transmission within the host population.

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Role of Circulating Immune Complexes in the Pathogenesis of Canine Leishmaniasis: New Players in Vaccine Development

Microorganisms ◽

10.3390/microorganisms9040712 ◽

2021 ◽

Vol 9 (4) ◽

pp. 712

Author(s):

Cristina Cacheiro-Llaguno ◽

Nuria Parody ◽

Marta R. Escutia ◽

Jerónimo Carnés

Keyword(s):

Immune Complexes ◽

Vaccine Development ◽

Correct Diagnosis ◽

Circulating Immune Complexes ◽

Response To Treatment ◽

Canine Leishmaniasis ◽

Leishmania Infection ◽

Serum Samples ◽

Humoral Immune

During canine visceral leishmaniasis (CanL), due to Leishmania infantum (L. infantum), uncontrolled infection leads to a strong humoral immune response. As a consequence of the production of high antibody levels and the prolonged presence of parasite antigens, circulating immune complexes (CIC) are formed, which can be deposited in certain organs and tissues, inducing vasculitis, uveitis, dermatitis and especially glomerulonephritis and renal failure. A method to detect CIC and quantify their levels in serum samples from dogs infected with L. infantum has been recently described. It allowed demonstration of a correlation between CIC levels and disease severity. Thus, CIC measurement may be useful for diagnosis, assessment of disease progression and monitoring response to treatment. This is an interesting finding, considering that there remains an urgent need for identification of novel biomarkers to achieve a correct diagnosis and for optimal disease staging of dogs suffering from Leishmania infection. The objective of the present review is to shed light on the role of CIC in CanL, as well as to highlight their potential use not only as diagnostic and prognostic biomarkers but also as a valuable tool in vaccine development and new immunotherapy strategies to prevent or control disease outcome.

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SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus

Communications Biology ◽

10.1038/s42003-021-01649-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Mikail Dogan ◽

Lina Kozhaya ◽

Lindsey Placek ◽

Courtney Gunter ◽

Mesut Yigit ◽

...

Keyword(s):

Specific Antibody ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

High Specificity ◽

Spike Protein ◽

Humoral Immune ◽

Specificity And Sensitivity ◽

Wide Range ◽

Specific Igg ◽

Negative Controls

AbstractDevelopment of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.

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Treatment of Toxoplasmosis and Neosporosis in Farm Ruminants: State of Knowledge and Future Trends

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666181002113617 ◽

2018 ◽

Vol 18 (15) ◽

pp. 1304-1323 ◽

Cited By ~ 11

Author(s):

Roberto Sánchez-Sánchez ◽

Patricia Vázquez ◽

Ignacio Ferre ◽

Luis Miguel Ortega-Mora

Keyword(s):

Vaccine Development ◽

Neospora Caninum ◽

Treatment Options ◽

Small Ruminants ◽

Additional Treatment ◽

Current Status ◽

Caninum Infection ◽

Zoonotic Parasites ◽

Toxoplasma Gondii Infection

Toxoplasmosis and neosporosis are closely related protozoan diseases that lead to important economic impacts in farm ruminants. Toxoplasma gondii infection mainly causes reproductive failure in small ruminants and is a widespread zoonosis, whereas Neospora caninum infection is one of the most important causes of abortion in cattle worldwide. Vaccination has been considered the most economic measure for controlling these diseases. However, despite vaccine development efforts, only a liveattenuated T. gondii vaccine has been licensed for veterinary use, and no promising vaccines against neosporosis have been developed; therefore, vaccine development remains a key goal. Additionally, drug therapy could be a valuable strategy for disease control in farm ruminants, as several drugs that limit T. gondii and N. caninum proliferation and dissemination have been evaluated. This approach may also be relevant to performing an initial drug screening for potential human therapy for zoonotic parasites. Treatments can be applied against infections in adult ruminants to minimize the outcomes of a primo-infection or the reactivation of a chronic infection during gestation or in newborn ruminants to avoid infection chronification. In this review, the current status of drug development against toxoplasmosis and neosporosis in farm ruminants is presented, and in an effort to promote additional treatment options, prospective drugs that have shown efficacy in vitro and in laboratory animal models of toxoplasmosis and neosporosis are examined.

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History of Diphtheria Vaccine Development

Corynebacterium diphtheriae and Related Toxigenic Species ◽

10.1007/978-94-007-7624-1_11 ◽

2013 ◽

pp. 225-238 ◽

Cited By ~ 3

Author(s):

Rino Rappuoli ◽

Enrico Malito

Keyword(s):

Vaccine Development ◽

History Of

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Immunoprofiles associated with controlled human malaria infection and naturally acquired immunity identify a shared IgA pre-erythrocytic immunoproteome

npj Vaccines ◽

10.1038/s41541-021-00363-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Andrea A. Berry ◽

Joshua M. Obiero ◽

Mark A. Travassos ◽

Amed Ouattara ◽

Drissa Coulibaly ◽

...

Keyword(s):

Malaria Infection ◽

Vaccine Development ◽

Protein Microarray ◽

Antibody Responses ◽

Liver Stage ◽

Human Malaria ◽

Controlled Human Malaria Infection ◽

Iga Antibody ◽

Potential Vaccine ◽

Antigen Protein

AbstractKnowledge of the Plasmodium falciparum antigens that comprise the human liver stage immunoproteome is important for pre-erythrocytic vaccine development, but, compared with the erythrocytic stage immunoproteome, more challenging to classify. Previous studies of P. falciparum antibody responses report IgG and rarely IgA responses. We assessed IgG and IgA antibody responses in adult sera collected during two controlled human malaria infection (CHMI) studies in malaria-naïve volunteers and in 1- to 6-year-old malaria-exposed Malian children on a 251 P. falciparum antigen protein microarray. IgG profiles in the two CHMI groups were equivalent and differed from Malian children. IgA profiles were robust in the CHMI groups and a subset of Malian children. We describe immunoproteome differences in naïve vs. exposed individuals and report pre-erythrocytic proteins recognized by the immune system. IgA responses detected in this study expand the list of pre-erythrocytic antigens for further characterization as potential vaccine candidates.

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