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Vaccines and Antibodies for Therapeutic Use in Cancers  [PDF]
G. P. Talwar, Jagdish C. Gupta, M. Diwan, J. Frick, S. K. Sharma, S. N. Wadhwa, R. M. Gupta, S. K. Gupta, Shilpi Purswani, Hemant K. Vyas
Journal of Cancer Therapy (JCT) , 2016, DOI: 10.4236/jct.2016.76040
Abstract: This review describes briefly the beneficial use of two vaccines developed by us for treatment of cancers. The vaccine against Luteinizing Hormone Releasing Hormone (LHRH) is effective in carcinoma of prostate as well as in breast cancers dependent on androgens and estrogens respectively. LHRH being identical in both males and females, the same vaccine is usable in both Prostate and Breast steroid hormones-dependent-cancers. Monoclonal antibodies are finding therapeutic utility in several cancers, and many have received Drugs Regulatory approval. The monoclonals developed by us against hCG and against epitopes present on androgen-independent castration resistant prostate cancers are briefly recapitulated. Anti-hCG antibodies kill several cancers expressing hCG. An example is given of A549 lung carcinoma. MoAb730 and MoAb7B2G10 kill DU-145 and PC-3 androgen-independent castration resistant prostate cancer cells. Some cancers such as MOLT-4, a T-lymphoblastic leukemia, though expressing hCG are not killed by PiPP, the high affinity anti-hCG antibody. Linking the antibody to curcumin however works like a “Magic Bullet”. All MOLT-4 cells are killed by this conjugate, the antibody homes selectively to cancer cells expressing hCG to deliver curcumin which exercises the killing effect. A recombinant vaccine, hCGβ-LTB (human chorionic gonadotropin subunit β linked to B subunit of heat-labile enterotoxin of E. coli) has been made, which induces high titre bioeffective antibodies not only in BalbC, but also in other genetic strains of mice. The vaccine employs autoclaved Mycobacterium indicus pranii (MiP) as adjuvant. MiP invigorates both humoral and cell mediated immune responses against Human chorionic gonadotropin (hCG). Besides being a potent adjuvant, MiP used alone heals anogenital warts in humans and has the property of preventing and curing SP2/O Myelomas in mice.
Immunogenicity and Protective Efficacy of a Polyvalent DNA Vaccine against Human Orthopoxvirus Infections Based on Smallpox Virus Genes  [PDF]
Rinat A. Maksyutov,Elena V. Gavrilova,Galina V. Kochneva,Sergei N. Shchelkunov
Journal of Vaccines , 2013, DOI: 10.1155/2013/618324
Abstract: DNA vaccines combining plasmids carrying the variola virus genes M1R, A30L, and F8L of intracellular virion surface membrane proteins as well as A36R and B7R of the extracellular virus envelope proteins under control of Rous sarcoma virus or cytomegalovirus promoters have been constructed. These DNA vaccines induced production of a high titers of vaccinia virus-neutralizing antibodies in mice similar to those elicited by the live vaccinia virus immunization. Mice vaccinated by created DNA vaccine were completely protected against a lethal (10 LD50) challenge with highly pathogenic ectromelia virus. These results suggest that such vaccine should be efficient in immunization of humans against smallpox. 1. Introduction The historically first method used for human protection against devastating smallpox epidemics was the so-called variolation, that is, an intracutaneous inoculation of healthy persons with infectious material from human smallpox cases. The disease thus induced had a shorter incubation period and a milder course as compared with the disease caused by a common respiratory transmission of this infection. The mortality rate after variolation was 0.5?2% versus 20?30% typical for the smallpox epidemics. The discovery of human vaccination using first cowpox virus (CPXV) and then vaccinia virus (VACV) had led to a considerable decrease in the severe side reactions [1, 2]. Taking into account the postvaccination complications caused by classical live vaccine involving VACV and confirmation of the global smallpox eradication, the World Health Organization recommended in 1980 to stop further vaccination against this infection [1]. Subsequent worldwide cessation of the vaccination against smallpox has created a most dangerous situation when the human population year by year becomes ever more unprotected not only from a potential infection with variola virus (VARV) as a result of a bioterrorism attack or reemergence of the virus in nature, but also from infection with other closely related orthopoxviruses, the natural reservoir of which is small rodents [3–5]. This is demonstrated by more frequent outbreaks of human orthopoxvirus infections caused by monkeypox virus (MPXV), CPXV, and VACV [6–10]. The absence of efficient antivirals makes the vaccine prevention the most important specific tool for control of the orthopoxvirus infections among humans. Use of the classical live VACV vaccine for mass vaccinations is now unacceptable because of a relatively large number of potential complications, especially taking into account the increased number of
Genomic Expression Libraries for the Identification of Cross-Reactive Orthopoxvirus Antigens  [PDF]
Lilija Miller, Marco Richter, Christoph Hapke, Daniel Stern, Andreas Nitsche
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021950
Abstract: Increasing numbers of human cowpox virus infections that are being observed and that particularly affect young non-vaccinated persons have renewed interest in this zoonotic disease. Usually causing a self-limiting local infection, human cowpox can in fact be fatal for immunocompromised individuals. Conventional smallpox vaccination presumably protects an individual from infections with other Orthopoxviruses, including cowpox virus. However, available live vaccines are causing severe adverse reactions especially in individuals with impaired immunity. Because of a decrease in protective immunity against Orthopoxviruses and a coincident increase in the proportion of immunodeficient individuals in today's population, safer vaccines need to be developed. Recombinant subunit vaccines containing cross-reactive antigens are promising candidates, which avoid the application of infectious virus. However, subunit vaccines should contain carefully selected antigens to confer a solid cross-protection against different Orthopoxvirus species. Little is known about the cross-reactivity of antibodies elicited to cowpox virus proteins. Here, we first identified 21 immunogenic proteins of cowpox and vaccinia virus by serological screenings of genomic Orthopoxvirus expression libraries. Screenings were performed using sera from vaccinated humans and animals as well as clinical sera from patients and animals with a naturally acquired cowpox virus infection. We further analyzed the cross-reactivity of the identified immunogenic proteins. Out of 21 identified proteins 16 were found to be cross-reactive between cowpox and vaccinia virus. The presented findings provide important indications for the design of new-generation recombinant subunit vaccines.
An Increasing Danger of Zoonotic Orthopoxvirus Infections  [PDF]
Sergei N. Shchelkunov
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003756
Abstract: On May 8, 1980, the World Health Assembly at its 33rd session solemnly declared that the world and all its peoples had won freedom from smallpox and recommended ceasing the vaccination of the population against smallpox. Currently, a larger part of the world population has no immunity not only against smallpox but also against other zoonotic orthopoxvirus infections. Recently, recorded outbreaks of orthopoxvirus diseases not only of domestic animals but also of humans have become more frequent. All this indicates a new situation in the ecology and evolution of zoonotic orthopoxviruses. Analysis of state-of-the-art data on the phylogenetic relationships, ecology, and host range of orthopoxviruses—etiological agents of smallpox (variola virus, VARV), monkeypox (MPXV), cowpox (CPXV), vaccinia (VACV), and camelpox (CMLV)—as well as the patterns of their evolution suggests that a VARV-like virus could emerge in the course of natural evolution of modern zoonotic orthopoxviruses. Thus, there is an insistent need for organization of the international control over the outbreaks of zoonotic orthopoxvirus infections in various countries to provide a rapid response and prevent them from developing into epidemics.
Polyclonal antibody cocktails generated using DNA vaccine technology protect in murine models of orthopoxvirus disease
Joseph W Golden, Marina Zaitseva, Senta Kapnick, Robert W Fisher, Malgorzata G Mikolajczyk, John Ballantyne, Hana Golding, Jay W Hooper
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-441
Abstract: Here, we demonstrated that the antibodies produced in vaccinated NHPs were sufficient to confer protection in a murine model of lethal Orthopoxvirus infection. We further explored the concept of using DNA vaccine technology to produce immunogen-specific polyclonal antibodies that could then be combined into cocktails as potential immunoprophylactic/therapeutics. Specifically, we used DNA vaccines delivered by muscle electroporation to produce polyclonal antibodies against the L1, A27, A33, and B5 in New Zealand white rabbits. The polyclonal antibodies neutralized both MV and EV in cell culture. The ability of antibody cocktails consisting of anti-MV, anti-EV, or a combination of anti-MV/EV to protect BALB/c mice was evaluated as was the efficacy of the anti-MV/EV mixture in a mouse model of progressive vaccinia. In addition to evaluating weight loss and lethality, bioimaging technology was used to characterize the spread of the VACV infections in mice. We found that the anti-EV cocktail, but not the anti-MV cocktail, limited virus spread and lethality.A combination of anti-MV/EV antibodies was significantly more protective than anti-EV antibodies alone. These data suggest that DNA vaccine technology could be used to produce a polyclonal antibody cocktail as a possible product to replace vaccinia immune globulin.Naturally occurring smallpox has been eradicated. However, the possibility that smallpox, caused by variola virus (VARV), or a genetically engineered Orthopoxvirus, might be reintroduced through a nefarious act remains a low-probability, but high-impact threat. Additionally, monkeypox virus (MPXV) is an emerging virus that causes endemic disease in central Africa and cowpox has caused sporadic serious cases of disease in Europe. These zoonotic viruses have the potential to spread and cause morbidity and mortality in animals and humans [1-4]. Examples of such unexpected long-range spread of these diseases include the monkeypox outbreak in midwestern United Sta
Serologic evidence of human orthopoxvirus infections in Sierra Leone
Adam MacNeil, Jason Abel, Mary G Reynolds, RR Lash, Richard Fonnie, Lansana D Kanneh, Willie Robert, Victor K Lungay, Augustine Goba, Lina M Moses, Inger K Damon, Kevin Karem, Daniel G Bausch
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-465
Abstract: To examine evidence of exposure to orthopoxviruses in the Kenema District of Sierra Leone, we collected and tested sera from 1596 persons by IgG ELISA and a subset of 313 by IgM capture ELISA. Eleven persons born after the cessation of smallpox vaccination had high orthopoxvirus-specific IgG values, and an additional 6 persons had positive IgM responses. No geographic clustering was noted.These data suggest that orthopoxviruses continue to circulate in Sierra Leone. Studies aimed at obtaining orthopoxvirus isolates and/or genetic sequences from rodents and symptomatic humans in the area are indicated.Orthopoxviruses are large DNA viruses in the family Poxviridae [1]. Included in the Orthopoxvirus genus are variola virus, the causative agent of smallpox; vaccinia virus, the live virus component of the smallpox vaccine; monkeypox virus, the causative agent of monkeypox; and as well as other zoonotic viruses, including many not known to cause human disease. Smallpox vaccination results in broadly reactive anti-orthopoxvirus serologic responses that persist for decades [2].Sierra Leone is a country of 6 million inhabitants on the west coast of Africa (Figure 1). In response to an outbreak of smallpox in Sierra Leone in 1967-1968, a large vaccination campaign was launched, resulting in vaccination coverage close to 80% [3]. Although we were unable to verify the precise date that routine smallpox vaccination ceased in Sierra Leone, veteran colleagues in the region put it at 1972-73. Smallpox was declared eradicated in 1980. Numerous cases of human monkeypox were detected in West Africa between 1970 and 1986, including a single case in Sierra Leone in 1970, but no cases have been reported since [4-7]. However, a monkeypox outbreak resulting in 47 confirmed and probable cases occurred in the United States in 2003, and was linked to a West African strain of the virus imported through a shipment of African mammals from Ghana [8-10].Despite the absence of reported human orthop
Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics  [PDF]
Scott Parker,Akbar M. Siddiqui,George Painter,Jill Schriewer,R. Mark Buller
Viruses , 2010, DOI: 10.3390/v2091918
Abstract: The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the “Animal Efficacy Rule”. One such challenge model uses ectromelia virus, an orthopoxvirus, whose natural host is the mouse and is the etiological agent of mousepox. The genetic similarity of ectromelia virus to variola and monkeypox viruses, the common features of the resulting disease, and the convenience of the mouse as a laboratory animal underscores its utility in the study of orthopoxvirus pathogenesis and in the development of therapeutics and prophylactics. In this review we outline how mousepox has been used as a model for smallpox. We also discuss mousepox in the context of mouse strain, route of infection, infectious dose, disease progression, and recovery from infection.
When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond
Nissin Moussatché,1,2 Clarissa R. Damaso,2 and Grant McFadden1
Journal of Infection in Developing Countries , 2008,
Abstract: The presence of zoonotic poxviruses in nature represents a potential human health risk that has to be re-evaluated by health authorities not only in developing countries, but also in many developed countries. For example, buffalopox virus infection remains to be a threat to humans and cattle in India, and monkeypox virus infection persists in several inhabited places in Africa and, more recently, in the USA. There are also a great number of zoonotic transmissions of cowpox virus from cats to humans in Europe. For almost a decade in Brazil, vaccinia-like viruses have been isolated from human and cattle infections. This review examines the ability of potentially pathogenic orthopoxviruses, including feral versions of vaccinia virus vaccine, to persist in nature and re-emerge for reasons we do not yet understand.
Experimental vaccines for sexually transmitted infections  [PDF]
Jovanovi? Marina,Karadagli? ?or?ije,Golu?in Zoran,Brki? Silvija
Medicinski Pregled , 2009, DOI: 10.2298/mpns0902042j
Abstract: Introduction. Sexually transmitted infections (STIs) are major global public health problems. Present strategies for prevention have limitations. Vaccines are an attractive addition to the current prevention armamentarium because they provide durable protection and do not require repetitive adherence to be effective. Challenges for vaccination include induction and long-term maintaince of mucosal immune responses in the female genital tract. Vaccines: a realistic goal?. For the time being, US Centers for Disease Control and Prevention have recommended only hepatitis and HPV immunization to be routinely offered. Final, III stage trials are underway on other prophylactic vaccines for human papillomavirus and genital herpes. Though vaccines against Chlamydia trachomatis and Neisseria gonorrhoeae are in early stages of development they do offer the hope of preventing pelvic inflammations. The high incidence of HIV-infection for which a vaccine would not be readily available, 'cries out' for an effective vaccine. Vaccines for HPV infections. According to a recent meta-analysis of worldwide prevalence data, vaccinating with HPV-16/18 VLP against HPV-16 and HPV-18 could prevent over 70% of invasive cervical cancer worldwide. The latest release of data from the phase III trial of a quadrivalent recombinant non-infectious vaccine HPV-6/11/ 16/18 L1 VLP, including HPV types 6,11,16,18 have given complete protection against HPV-16/18-related cervical intraepithelial neoplasias 1, 2/3, and adenocarcinoma in situ and cancer through 2 years of post-vaccination follow up. Conclusion. Despite the fact that the development of vaccines for STI prevention was rather slow in the past, the ideal vaccine would decrease transmission of the infection between partners and would prevent complications of disease. Moreover, in future decades, increasingly successful universal vaccination of newborns and children will substantially reduce the need for vaccination of persons with specific risk factors, including sexual risk.
Vaccines against papillomavirus infections and disease
Villa,Luisa Lina;
Salud Pública de México , 2003, DOI: 10.1590/S0036-36342003000900019
Abstract: squamous cell carcinoma of the uterine cervix is the second cause of cancer-related deaths in women, the higher incidence being observed in developing countries. infection with oncogenic types of human papillomavirus (hpv) is considered the major risk factor for the development of malignancies in the uterine cervix. however, hpv is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenic process, both present in the environment and from the host. studies performed in animals, and more recently in humans, indicate that vaccination against the capsid proteins of the virus can prevent efficiently from infection. furthermore, therapeutic vaccines are under investigation aiming the regression of papillomavirus induced tumors. the scientific basis for the development of papillomavirus vaccines and present status of clinical trials will be addressed in this chapter.
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