Browsing by Author "Bottazzi, Maria Elena"
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Item A Recombinant Protein XBB.1.5 RBD/Alum/CpG Vaccine Elicits High Neutralizing Antibody Titers against Omicron Subvariants of SARS-CoV-2(2023) Thimmiraju, Syamala Rani; Adhikari, Rakesh; Villar, Maria Jose; Lee, Jungsoon; Liu, Zhuyun; Kundu, Rakhi; Chen, Yi-Lin; Sharma, Suman; Ghei, Karm; Keegan, Brian; Versteeg, Leroy; Gillespie, Portia M.; Ciciriello, Allan; Islam, Nelufa Y.; Poveda, Cristina; Uzcategui, Nestor; Chen, Wen-Hsiang; Kimata, Jason T.; Zhan, Bin; Strych, Ulrich; Bottazzi, Maria Elena; Hotez, Peter J.; Pollet, Jeroen(1) Background: We previously reported the development of a recombinant protein SARS-CoV-2 vaccine, consisting of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, adjuvanted with aluminum hydroxide (alum) and CpG oligonucleotides. In mice and non-human primates, our wild-type (WT) RBD vaccine induced high neutralizing antibody titers against the WT isolate of the virus, and, with partners in India and Indonesia, it was later developed into two closely resembling human vaccines, Corbevax and Indovac. Here, we describe the development and characterization of a next-generation vaccine adapted to the recently emerging XBB variants of SARS-CoV-2. (2) Methods: We conducted preclinical studies in mice using a novel yeast-produced SARS-CoV-2 XBB.1.5 RBD subunit vaccine candidate formulated with alum and CpG. We examined the neutralization profile of sera obtained from mice vaccinated twice intramuscularly at a 21-day interval with the XBB.1.5-based RBD vaccine, against WT, Beta, Delta, BA.4, BQ.1.1, BA.2.75.2, XBB.1.16, XBB.1.5, and EG.5.1 SARS-CoV-2 pseudoviruses. (3) Results: The XBB.1.5 RBD/CpG/alum vaccine elicited a robust antibody response in mice. Furthermore, the serum from vaccinated mice demonstrated potent neutralization against the XBB.1.5 pseudovirus as well as several other Omicron pseudoviruses. However, regardless of the high antibody cross-reactivity with ELISA, the anti-XBB.1.5 RBD antigen serum showed low neutralizing titers against the WT and Delta virus variants. (4) Conclusions: Whereas we observed modest cross-neutralization against Omicron subvariants with the sera from mice vaccinated with the WT RBD/CpG/Alum vaccine or with the BA.4/5-based vaccine, the sera raised against the XBB.1.5 RBD showed robust cross-neutralization. These findings underscore the imminent opportunity for an updated vaccine formulation utilizing the XBB.1.5 RBD antigen.Item A trivalent protein-based pan-Betacoronavirus vaccine elicits cross-neutralizing antibodies against a panel of coronavirus pseudoviruses(Springer Nature, 2024) Thimmiraju, Syamala Rani; Adhikari, Rakesh; Redd, JeAnna R.; Villar, Maria Jose; Lee, Jungsoon; Liu, Zhuyun; Chen, Yi-Lin; Sharma, Suman; Kaur, Amandeep; Uzcategui, Nestor L.; Ronca, Shannon E.; Chen, Wen-Hsiang; Kimata, Jason T.; Zhan, Bin; Strych, Ulrich; Bottazzi, Maria Elena; Hotez, Peter J.; Pollet, JeroenThe development of broad-spectrum coronavirus vaccines is essential to prepare for future respiratory virus pandemics. We demonstrated broad neutralization by a trivalent subunit vaccine, formulating the receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 XBB.1.5 with Alum and CpG55.2. Vaccinated mice produced cross-neutralizing antibodies against all three human Betacoronaviruses and others currently exclusive to bats, indicating the epitope preservation of the individual antigens during co-formulation and the potential for epitope broadening.Item COVID-19 in the Americas and the erosion of human rights for the poor(Public Library of Science, 2020) Hotez, Peter J.; Huete-Perez, Jorge A.; Bottazzi, Maria Elena; James A Baker III Institute for Public PolicyItem Human Schistosomiasis Vaccines as Next Generation Control Tools(MDPI, 2023) Hotez, Peter J.; Bottazzi, Maria Elena; James A. Baker III Institute for Public PolicyHuman schistosomiasis remains one of the most important yet neglected tropical diseases, with the latest estimates from the Global Burden of Disease Study indicating that over 140 million people are infected with schistosomes [...]Item Neglected Tropical Diseases among the Association of Southeast Asian Nations (ASEAN): Overview and Update(2015) Hotez, Peter J.; Bottazzi, Maria Elena; Strych, Ulrich; Chang, Li-Yen; Lim, Yvonne A.L.; Goodenow, Maureen M.; AbuBakar, Sazaly; James A. Baker III Institute for Public PolicyThe ten member states of the Association of Southeast Asian Nations (ASEAN) constitute an economic powerhouse, yet these countries also harbor a mostly hidden burden of poverty and neglected tropical diseases (NTDs). Almost 200 million people live in extreme poverty in ASEAN countries, mostly in the low or lower middle-income countries of Indonesia, the Philippines, Myanmar, Viet Nam, and Cambodia, and many of them are affected by at least one NTD. However, NTDs are prevalent even among upper middle-income ASEAN countries such as Malaysia and Thailand, especially among the indigenous populations. The three major intestinal helminth infections are the most common NTDs; each helminthiasis is associated with approximately 100 million infections in the region. In addition, more than 10 million people suffer from either liver or intestinal fluke infections, as well as schistosomiasis and lymphatic filariasis (LF). Intestinal protozoan infections are widespread, while leishmaniasis has emerged in Thailand, and zoonotic malaria (Plasmodium knowlesi infection) causes severe morbidity in Malaysia. Melioidosis has emerged as an important bacterial NTD, as have selected rickettsial infections, and leptospirosis. Leprosy, yaws, and trachoma are still endemic in focal areas. Almost 70 million cases of dengue fever occur annually in ASEAN countries, such that this arboviral infection is now one of the most common and economically important NTDs in the region. A number of other arboviral and zoonotic viral infections have also emerged, including Japanese encephalitis; tick-borne viral infections; Nipah virus, a zoonosis present in fruit bats; and enterovirus 71 infection. There are urgent needs to expand surveillance activities in ASEAN countries, as well as to ensure mass drug administration is provided to populations at risk for intestinal helminth and fluke infections, LF, trachoma, and yaws. An ASEAN Network for Drugs, Diagnostics, Vaccines, and Traditional Medicines Innovation provides a policy framework for the development of new control and elimination tools. Together with prominent research institutions and universities, the World Health Organization (WHO), and its regional offices, these organizations could implement important public health improvements through NTD control and elimination in the coming decade.Item Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain–based vaccine candidate, RBD219-N1C1(Springer Nature, 2021) Lee, Jungsoon; Liu, Zhuyun; Chen, Wen-Hsiang; Wei, Junfei; Kundu, Rakhi; Adhikari, Rakesh; Rivera, Joanne Altieri; Gillespie, Portia M.; Strych, Ulrich; Zhan, Bin; Hotez, Peter J.; Bottazzi, Maria Elena; James A. Baker III Institute for Public PolicyA SARS-CoV-2 RBD219-N1C1 (RBD219-N1C1) recombinant protein antigen formulated on Alhydrogel® has recently been shown to elicit a robust neutralizing antibody response against SARS-CoV-2 pseudovirus in mice. The antigen has been produced under current good manufacturing practices (cGMPs) and is now in clinical testing. Here, we report on process development and scale-up optimization for upstream fermentation and downstream purification of the antigen. This includes production at the 1-L and 5-L scales in the yeast, Pichia pastoris, and the comparison of three different chromatographic purification methods. This culminated in the selection of a process to produce RBD219-N1C1 with a yield of >400 mg per liter of fermentation with >92% purity and >39% target product recovery after purification. In addition, we show the results from analytical studies, including SEC-HPLC, DLS, and an ACE2 receptor binding assay that were performed to characterize the purified proteins to select the best purification process. Finally, we propose an optimized upstream fermentation and downstream purification process that generates quality RBD219-N1C1 protein antigen and is fully scalable at a low cost.Item “Running the Gauntlet”: Formidable challenges in advancing neglected tropical diseases vaccines from development through licensure, and a “Call to Action”(Taylor & Francis, 2019) Bottazzi, Maria Elena; Hotez, Peter J.; James A. Baker III Institute of Public PolicyTranslational science for new biotechnologies (e.g. drugs, vaccines, devices, or diagnostics) depend on the development of a robust ‘business case’. This is driven by complex scientific, technical, logistical, financial and operational elements to determine the feasibility and probability of traversing the “valleys of death” leading to licensure. The potential results in terms of profitability and financial realization, called ‘product value proposition’ play a crucial role in establishing incentives for investment during and after development. With this review, our goal is to summarize the challenges in taking vaccines against neglected tropical diseases (NTDs) from development through licensure and provide a perspective that these vaccines can have measurable public health and economic profitability and market success. Understanding these processes and its challenges would open the opportunity to accelerate and advance these essential NTD vaccines through the last mile towards licensure and for the delivery to afflicted populations in low- and middle-income countries.Item The Gulf of Mexico: A “Hot Zone” for Neglected Tropical Diseases?(Public Library of Science, 2015) Hotez, Peter J.; Bottazzi, Maria Elena; Dumonteil, Eric; Buekens, Pierre; James A. Baker III Institute for Public PolicyItem The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection(Public Library of Science, 2023) Nguyen, Duc Minh; Poveda, Cristina; Pollet, Jeroen; Gusovsky, Fabian; Bottazzi, Maria Elena; Hotez, Peter J.; Jones, Kathryn MarieBackground Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ. Methodology Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25μg Tc24-C4 protein/ 5μg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum. Results Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact. Conclusions These data confirm toxicity associated with curative doses of BNZ and suggest that while dose sparing low BNZ plus vaccine treatment does not reduce parasite burdens, it better preserves liver health.Item Toxocariasis in North America: A Systematic Review(Public Library of Science, 2014) Lee, Rachel M.; Moore, Laura B.; Bottazzi, Maria Elena; Hotez, Peter J.; James A. Baker III Institute for Public PolicyToxocariasis is an important neglected tropical disease that can manifest as visceral or ocular larva migrans, or covert toxocariasis. All three forms pose a public health problem and cause significant morbidity in areas of high prevalence. To determine the burden of toxocariasis in North America, we conducted a systematic review of the literature following PRISMA guidelines. We found 18 articles with original prevalence, incidence, or case data for toxocariasis. Prevalence estimates ranged from 0.6% in a Canadian Inuit community to 30.8% in Mexican children with asthma. Commonly cited risk factors included: African-American race, poverty, male sex, and pet ownership or environmental contamination by animal feces. Increased prevalence of Toxocara spp. infection was linked in a group of case control studies conducted in Mexico to several high risk groups including waste pickers, asthmatic children, and inpatient psychiatry patients. Further research is needed to determine the true current burden of toxocariasis in North America; however the prevalence estimates gathered in this review suggest that the burden of disease is significant.Item Vaccine-linked chemotherapy improves cardiac structure and function in a mouse model of chronic Chagas disease(Frontiers, 2023) Jones, Kathryn M.; Mangin, Elise N.; Reynolds, Corey L.; Villanueva, Liliana E.; Cruz, Julio Vladimir; Versteeg, Leroy; Keegan, Brian; Kendricks, April; Pollet, Jeroen; Gusovsky, Fabian; Bottazzi, Maria Elena; Hotez, Peter J.; James A. Baker III Institute for Public PolicyIntroduction: Chagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. We previously demonstrated in acute infection models that this strategy parasite specific immune responses, and reduced parasite burdens and cardiac pathology. Here, we tested our vaccine-linked chemotherapy strategy in a mouse model of chronic T. cruzi infection to evaluate the effect on cardiac function.Methods: Female BALB/c mice infected with 500 blood form T. cruzi H1 strain trypomastigotes were treated beginning 70 days after infection with a low dose of BNZ and either low or high dose of vaccine, in both sequential and concurrent treatments streams. Control mice were untreated, or administered only one treatment. Cardiac health was monitored throughout the course of treatment by echocardiography and electrocardiograms. Approximately 8 months after infection, endpoint histopathology was performed to measure cardiac fibrosis and cellular infiltration.ResultsVaccine-linked chemotherapy improved cardiac function as evidenced by amelioration of altered left ventricular wall thickness, left ventricular diameter, as well as ejection fraction and fractional shortening by approximately 4 months of infection, corresponding to two months after treatment was initiated. At study endpoint, vaccine-linked chemotherapy reduced cardiac cellular infiltration, and induced significantly increased antigen specific IFN-γ and IL-10 release from splenocytes, as well as a trend toward increased IL-17A.Discussion: These data suggest that vaccine-linked chemotherapy ameliorates changes in cardiac structure and function induced by infection with T. cruzi. Importantly, similar to our acute model, the vaccine-linked chemotherapy strategy induced durable antigen specific immune responses, suggesting the potential for a long lasting protective effect. Future studies will evaluate additional treatments that can further improve cardiac function during chronic infection.