Vaccines against chronic Trypanosoma cruzi infection: progress, challenges and future directions

The manuscript "Vaccination with parasite-specific TcTASV proteins combined with recombinant baculovirus as a delivery platform protects against acute and chronic Trypanosoma cruzi infection" proves to be promising in delivering a vaccine candidate against Trypanosoma cruzi, which causes Chagas disease. The authors discuss combination of parasite specific proteins alongside a baculovirus platform used as a delivery displaying one such protein on the capsid. The combination works successfully, with vaccinated mice surviving a lethal challenge with T. cruzi and presenting reduced parasitic load in chronic infection. It remains to be seen as to the success of the vaccine against other strains of T. cruzi as well as the durability of the immune response (Simone Frédérique Brenière, 2016).Animal models are essential and functional during the discovery and development phases for a vaccine, but eventually all vaccines must prove their mettle in humans. Manuscripts "Effectiveness of two-dose vs. one-dose varicella vaccine in children in Shanghai, China: a prospective cohort study" and "TRAIL and IP-10 dynamics in pregnant women post COVID-19 vaccination: associations with neutralizing antibody potency" are both studies in humans, although with differences. The former is a clinical trial that compares the effectiveness of one vs two doses of varicella vaccine in children in Shanghai China and concludes that two doses are more effective than one. The latter manuscript studies the dynamics of biomarkers for COVID-19 infection -TRAIL and IP-10 in pregnant women post COVID-19 vaccination as well as neutralizing antibody inhibition against COVID strains. These two manuscripts are also of special significance considering they study the course of vaccination in children and pregnant women, both vulnerable groups that merit additional analysis (Marshall, 2016;Örtqvist, 2010).Although the development of a successful vaccine represents a significant challenge, these articles all bring forward ways in which targets/biomarkers (S. Sohail Ahmed, 2011)can be identified that enable scientists and clinicians the tools to develop vaccines and therapeutics. Finally, vaccine and therapeutic research is an exciting field -rapidly evolving, harnessing new technologies to help reduce the burden of several diseases or to eliminate them entirely from our communities.

Chagas Disease Recommendations for Solid-Organ Transplant Recipients and Donors.

O objetivo do estudo foi verificar os aspectos nutricionais associados à infecção crônica pelo Trypanosoma cruzi entre os participantes da linha de base da coorte de idosos de Bambuí, Minas Gerais, Brasil. A análise incluiu 84,9% (1.479) de todos os residentes com 60 anos ou mais na cidade em 1997. A infecção pelo Tr. cruzi foi avaliada por três testes sorológicos e o perfil nutricional foi caracterizado por variáveis antropométricas e bioquímicas. As associações foram avaliadas pelas razões de prevalência e intervalos de 95% de confiança, utilizando a regressão de Poisson robusta e ajustando por potenciais fatores de confusão. A infecção foi observada em 38,1% dos idosos. Todas as variáveis antropométricas apresentaram associação significativa com a infecção, evidenciando menores valores entre os idosos com sorologia positiva. As variáveis bioquímicas não foram associadas ao evento estudado. Os resultados evidenciaram a concomitância da doença de Chagas crônica e pior estado nutricional nessa população, reforçando a importância da avaliação nutricional entre idosos com infecção crônica pelo Tr. cruzi.

Chagas disease is caused by infection with the protozoan pathogen, Trypanosoma cruzi. The only approved therapeutics for treating Chagas disease are two nitroheterocyclic compounds (benznidazole and nifurtimox) that are suboptimal due to poor curative activity for chronic Chagas disease and high rates of adverse drug reactions. Sterol 14-demethylase inhibitors include azole antifungal drugs such as ketoconazole, fluconazole, itraconazole, and others. The first reports of potent activity of azole antifungal drugs against Trypanosoma cruzi came out about 25 years ago. Since then, a sizeable literature has accumulated on this topic. Newer triazole compounds such as posaconazole and D0870 have been shown to be effective at curing mice with chronic Trypanosoma cruzi infection. Small clinical studies with-ketoconazole or itraconazole in humans with chronic Chagas disease have not demonstrated significant curative activity. However, there is good reason for optimism that newer compounds with greater potency and improved pharmacokinetic properties might be more efficacious. Data have been published demonstrating synergistic activity of azole drugs with various other compounds, indicating that combination chemotherapy may be an effective strategy as this field moves ahead. In light of the near absence of adequate therapeutics for curing patients with chronic Chagas disease, additional effort to develop better drugs needs to be a priority.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that Parp1 depletion enhances cardiac health by regulating CD8+T cell response against Trypanosoma cruzi (Tc) infection. For this, Parp1 -/- and wild-type (WT) mice were challenged with Tc and euthanized at acute and chronic phases of parasite replication and CD development, respectively. Parp1 -/- mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. Parp1 -/- enhanced the maturation and stability of metabolically reprogrammed CD8+ effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8+T cells, altered the PD1:PDL1 stoichiometric ratio between CD8+T and antigen-presenting cells, and promoted CD8+T cell longevity and function during chronic Tc infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis.

Safety and immunogenicity of a recombinant vaccine against Trypanosoma cruzi in Rhesus macaques

BackgroundThe main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis.Methodology/Principal FindingsThe expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3+, CD4+, CD8+, CD45RO+) with a low grade of differentiation (CD27+, CD57−, CD45RA−, PD-1−). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3+ cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3+ T cells, assessed by Ki67 staining, was found.Conclusions/SignificanceThe quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection.

To describe new developments in blood-bank screening and management of patients with chronic Trypanosoma cruzi infection in the United States. The first US Food and Drug Administration licensed serological test for T. cruzi blood screening went into widespread usage in January 2007. More than 500 confirmed T. cruzi-infected donations were detected by mid-June 2008. Until recently, drug therapy was recommended for acute and congenital infections, but seldom for chronic infections, which were believed to respond poorly. However, in the 1990s, efficacy was demonstrated in two placebo-controlled trials of benznidazole in children with chronic T. cruzi infection. In 2006, a nonrandomized, nonblinded trial demonstrated that benznidazole treatment may slow progression of cardiomyopathy and decrease mortality risk in infected adults. Blood-bank screening will continue to detect T. cruzi-infected donors. Based on recent data, antitrypanosomal treatment is recommended for all acute and congenital T. cruzi infections, reactivated infection, and chronically infected children. In adults aged 19-50 years without advanced heart disease, treatment should generally be offered; management should be individualized for older adults. Less toxic, more effective drugs, a sensitive, specific assay for response to treatment, and improved healthcare access would promote more effective management.

Trypanosoma cruzi infection is characterized by chronic parasitism of non-lymphoid tissues and is rarely eliminated despite potent adaptive immune responses. This failure to cure has frequently been attributed to a loss or impairment of anti-T. cruzi T cell responses over time, analogous to the T cell dysfunction described for other persistent infections. In this study, we have evaluated the role of CD8+ T cells during chronic T. cruzi infection (>100 dpi), with a focus on sites of pathogen persistence. Consistent with repetitive antigen exposure during chronic infection, parasite-specific CD8+ T cells from multiple organs expressed high levels of KLRG1, but exhibit a preferential accumulation of CD69+ cells in skeletal muscle, indicating recent antigen encounter in a niche for T. cruzi persistence. A significant proportion of CD8+ T cells in the muscle also produced IFNγ, TNFα and granzyme B in situ, an indication of their detection of and functional response to T. cruzi in vivo. CD8+ T cell function was crucial for the control of parasite burden during chronic infection as exacerbation of parasite load was observed upon depletion of this population. Attempts to improve T cell function by blocking PD-1 or IL-10, potential negative regulators of T cells, failed to increase IFNγ and TNFα production or to enhance T. cruzi clearance. These results highlight the capacity of the CD8+ T cell population to retain essential in vivo function despite chronic antigen stimulation and support a model in which CD8+ T cell dysfunction plays a negligible role in the ability of Trypanosoma cruzi to persist in mice.

Methods for detecting parasitemia in chronic Trypanosoma cruzi infection are either insensitive or nonquantitative. The polymerase chain reaction (PCR), used to detect parasite kinetoplast (k) minicircle DNA, has been shown to be virtually 100% sensitive and specific in chronically infected persons. This technique has now been modified to be quantitative by using a competitor DNA. The competitive PCR yields equal amounts of kDNA and competitor PCR products when they are mixed in equimolar ratios. Thus, the amount of parasites can be estimated from the quantity of competitor DNA at the equivalency point. Blood from 5 chronically infected mice gave results consistent with 3-260 parasites/mL, and blood from 1 chronically infected person yielded 4 parasites/mL. These are the first quantitative estimates of parasitemia in chronic T. cruzi infection. This technique could be useful for studying the natural history of T. cruzi infection and the response to therapy.

Hepatitis B and hepatitis C infections are prevalent worldwide with significant cost to the health sector, which could be substantially reduced with the implementation of few well-selected measures. The Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN) Working Group proposes 3 main priorities for medical interventions, namely universal hepatitis B immunisation, multicentric international trials on safety and efficacy of new drugs for treatment of chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infections in children, and development and implementation of age- and phase-specific guidelines for management of CHB infection. Education is essential to reduce hepatitis B and hepatitis C burden, and specific programs should be provided to increase public awareness on transmission and prevention of these infections. FISPGHAN also emphasizes the development of electronic learning programs for doctors on the management of hepatitis B and C infections along with the proper referral system for these patients. FISPGHAN has endorsed research and development of new drugs on the management of hepatitis B in children besides development of an effective vaccine against hepatitis C infection. There is also a need for the development of a vaccine for nonresponders to available hepatitis B vaccine. SUMMARY OF THE PROBLEM Approximately 60% of the world's population live in areas where hepatitis B virus (HBV) infection is highly endemic, including China (total population 1.3 billion), Indonesia (222 million), Nigeria (132 million), and much of the rest of Asia and Africa (1). A vaccine against hepatitis B, made of recombinant hepatitis B surface antigen (HBsAg), has proven to be extremely effective in most cases. To realise global prevention of the spread of hepatitis B, there is a need for the implementation of universal immunisation with hepatitis B vaccine, including in countries in which the immunisation is presently not provided. There is also a need for the development of an effective vaccine against hepatitis B for immunocompromised patients and for those (approximately 5%) who do not develop protective titres of antibody, despite receiving vaccine made of recombinant HBsAg. For the timely detection of cases of hepatitis B, widespread screening programs need to be in place especially targeting pregnant women and high-risk children to prevent vertical spread and decrease morbidity and mortality. There is a need to better understand the maternal/neonatal risk factors associated with transmission of infection to babies. The treatment of hepatitis B in children mainly compromises interferon/peginterferon and antivirals, lamivudine and adefovir, which have not been effective in terms of the success rate of seroconversion. According to guidelines, the time of onset of treatment should be dependent on the immune response. Drugs should be started in the immune-responsive phase. Most children are in the immunotolerant phase, during which liver disease is likely to progress further. The longer the disease persists, the greater the likelihood of developing hepatocellular carcinoma and greater the morbidity and mortality (2,3). There is an urgent need for the development of effective drugs for the treatment of hepatitis B in children and for validating the use of drugs already approved for use in adults such as telbivudine, tenofovir, and entecavir by carrying out multicentre international trials with newer therapies for hepatitis B (4). Hepatitis C virus (HCV) has worldwide distribution, occurring among people of all ages, sex, races, and regions of the world (5). The socioeconomic burden of HCV has not yet been defined in most countries. Where the epidemiology of hepatitis C has been studied, the consequences of CHC and end-stage liver cirrhosis have been shown to increasingly affect national health systems. Since the first reports in the early 1990s, the data on HCV prevalence remain disappointingly limited. Information is still inadequate in many countries and most prevalence studies are limited to specific subpopulations, (eg, pregnant women, blood donors, hospital inpatients), with only a few studies using sampling techniques that represent the entire population. There is an urgent need for the development of an effective vaccine against HCV infection. HBV and HCV are transmitted through percutaneous or parenteral contact with infected blood, body fluids, and by sexual contact. Screening of blood products using nucleic acid testing in blood banks is available in most developed countries and this should be adopted by developing countries to reduce blood transfusion–transmitted infection. To optimise and improve care, international guidelines for the management of hepatitis B and C in children, which could be universally followed, are needed together with an implementation plan. For the success of the preventive measures for hepatitis B and hepatitis C, general awareness of these infections is required. Knowledge by the public will promote the use of safe practices and hygiene to prevent the spread of infection. Awareness programs should be run on a mass scale to educate the public about these viruses, the disease caused by them, and long-term consequences. General physicians should be regularly updated through training programs and continuing medical education (CME). In addition, to optimise care, there needs to be regional/national networks and referral systems in place so that children, and at least those with severe or complicated disease, are being managed by experts (Table 1).Table 1: Table of prioritiesHEPATITIS B Hepatitis B is one of the most common infectious diseases in the world. It is estimated that 40% of the world's population has had contact with or are carriers of HBV, which corresponds to an estimated 350 million HBV carriers. The global epidemiology of HBV infection has traditionally been described according to the 3 categories of endemic rates: high (>8%), intermediate (2%–7%), and low (<2%), depending on the proportion of the population that is seropositive for HBsAg. The HBV endemic rate often correlates with the predominant mode of transmission. Approximately 60% of the world's population live in areas where HBV infection is highly endemic, including China (total population 1.3 billion), Indonesia (222 million), Nigeria (132 million), and much of the rest of Asia and Africa. Approximately 600,000 people die each year because of the acute or chronic consequences of hepatitis B. Despite the availability of effective HBV vaccines, hepatitis B remains a major global health problem. This situation is particularly serious in developing countries, especially because a significant percentage of the population does not have access to the vaccine or does not return for the required booster doses. A number of approaches are being tested to minimise this problem including needle-free immunisation. Treatment of Hepatitis B The primary treatment goals for children with hepatitis B are to strengthen the immune system so that it can effectively prevent the virus from replicating, and hence achieve an undetectable HBV viral load, thus halting any liver damage. It also produces the surface antibody (HBsAb), which indicates recovery from the infection. In addition to slowing liver disease in affected children, the major goal is to eradicate the disease in the paediatric population today to prevent cirrhosis and liver cancer in the adults of tomorrow. Unfortunately, treatments available for hepatitis B infection in children so far have had limited success. There are only a handful of paediatric clinical trials taking place to test drugs on children that so far have been used only in adults. Few studies have followed large numbers of children with CHB infections and even fewer have tracked children for ≥1 decade after treatment. When to treat hepatitis B in children is also an area of debate within the medical research and treatment communities. The only new drugs approved by the US Food and Drug Administration to treat hepatitis B in children are standard interferon, lamivudine and adefovir (for children older than 12 years), and entecavir and telbivudine (for children older than 16 years). Because presently these newer drugs are not recommended to be used on children younger than age 12 years, studies are needed in younger children. There is also a need to develop new effective drugs specifically to treat hepatitis B in children. A large proportion of infected children are in the immune-tolerant phase, in which the presently available drug therapy is ineffective. Research is needed to further study the immunological abnormalities in the immune-tolerant phase of hepatitis B and developing appropriate immunomodulatory therapies. The major objective of hepatitis B immunisation is the prevention of chronic infection, which leads to cirrhosis and hepatocellular carcinoma because HBV-related cirrhosis and hepatocellular carcinoma usually occur in adults who were infected with HBV during their childhood. The significant benefits of HBV vaccination are therefore only seen decades later. Taiwan is perhaps the best example of a, previously, highly endemic area where a substantial and measurable reduction in disease burden has resulted from a long-standing policy of universal childhood hepatitis B vaccination. HBsAg seroprevalence among Taiwanese children decreased from 9.8% in 1984, the year when universal infant immunisation began, to 0.7% in 1999. The average annual incidence of hepatocellular carcinoma among children ages 6 to 14 years in 1981–1986 (reflecting the prevaccine era) was 0.7/100,000, whereas in 1990–1994 (the postvaccine era) it was 0.36/100,000 (P < 0.01). In the period before routine vaccination (1974–1983) and the postvaccination era (1984–1999), mortality from hepatocellular carcinoma decreased 60% to 70% among children. In addition, mortality caused by fulminant hepatitis among infants decreased significantly. In Gambia, childhood HBsAg seroprevalence has decreased from 10% to 0.6% since the introduction of routine infant and childhood vaccination in 1986. In countries with intermediate endemicity such as Malaysia, which introduced universal infant vaccination in 1990, HBsAg seroprevalence among schoolchildren (ages 7–12 years) decreased from 1.6% in 1997 to 0.3% in 2003. Population-based surveillance data in Italy showed a decline in the incidence of acute hepatitis B from 11/100,000 in 1987 to 3/100,000 subjects in 2000. In addition, the overall prevalence of chronic HBV infection decreased from 13.4% in 1978 to 3.7% in 1997. The most dramatic effect of hepatitis B immunisation in the United States was seen in the Alaska Native community. In Bristol Bay, Alaska, before routine immunisation, 7.6% of children had serologic evidence of resolved infection by 9 years of age and 3.2% of children were chronically infected. Ten years after the onset of routine immunisation, no child younger than 10 years was chronically infected and only 1.5% had evidence of resolved infection. Similar seroprevalence declines have been observed in other US communities with traditionally high rates of disease. In children of Asian immigrants living in Georgia, HBV seroprevalence decreased from >20% before 1992 to 1.9% in 2001. National surveillance for acute hepatitis B in the United States is also consistent with an overall decline in new HBV infections. In 2004, the incidence of acute hepatitis B was 2.1/100,000 population (6212 cases), the lowest ever reported in the United States, representing a 75% decline since 1990. The most dramatic declines have occurred in children to whom recommendations for routine infant and adolescent catch-up vaccination were applied. Hepatitis B incidence declined 94% (from 3.0/100,000 to 0.19/100,000) in subjects younger than 20 years of age from 1990 to 2004. All these mounting data strongly confirm that the promotion of universal immunisation is of the utmost importance in decreasing the prevalence of hepatitis B irrespective of the endemic rate of the region. Immunocompromised patients, however, do not produce an effective immune response to hepatitis B vaccine. There is a need to develop effective vaccines for use in these patients. Prevention and Early Detection of Hepatitis B and C in High-risk Groups The vertical transmission of hepatitis B and, to a less extent, of hepatitis C is high in endemic areas. Most of the children who contract hepatitis B via the vertical route become chronically infected. The chances of CHC are also higher in these children. Screening child-bearing women for HBV and HCV and putting in place appropriate measures, including exclusive breast-feeding, can prevent vertical transmission and also lead to early detection. Screening high-risk groups, such as children who are immunodeficient, those receiving chemotherapy, taking steroids, or are malnourished would lead to early detection and improved management and contribute to prevention. Public awareness of the transmission and prevention of HBV and HCV is crucial in decreasing the incidence and prevalence of the disease. Education in various forms to increase public awareness of transmission and prevention is therefore extremely important. The ongoing education of general paediatricians and physicians is needed to increase and update their knowledge about hepatitis B and C with the aim of optimising management of these patients, including appropriate referral to specialists. Finally, there is a need for developing and implementing evidence-based international guidelines for preventing and managing hepatitis B and hepatitis C in children worldwide. HEPATITIS C The prevalence of hepatitis C is approximately 170 to 200 million individuals worldwide. Published data suggest that most populations in America, western Europe, and southeast Asia have prevalence rates of antibody to HCV (anti-HCV) of <2.5%. Anti-HCV prevalence rates for eastern Europe average from 1.5% to 5%, those for the western Pacific region from 2.5% to 4.9%, and those for the Middle East and central Asia from 1% to >12%. In terms of absolute numbers, the majority of infected people live in central/southeast Asia and the western Pacific regions, a pattern similar to that for CHB infection (6–8). The effect of hepatitis C on health costs is considerable. In addition, one of the major hurdles in the eradication/reduction of the burden of hepatitis C is the lack of hepatitis C vaccine. To date, hepatitis C has been difficult to target with a vaccine because there are many different strains of the virus. In addition, like human immunodeficiency virus (HIV), the HCV mutates rapidly and exists as a complex family of mutated viruses within each infected individual, allowing the infecting virus to escape control by the immune system. This makes it difficult to identify which part of the virus should be targeted for developing an effective vaccine production. In the United States, the present estimate of the annual costs of acute and chronic hepatitis C is estimated to exceed US$600 million, and, during the period 2010–2019, the total costs are expected to reach US$184 billion, giving an indication of how important the burden of chronic HCV infection can be for the national health systems, even in a low-endemicity country (1.8%) (9). The European Monitoring Centre for Drugs and Drug Addiction estimated the HCV-related costs in 10 European Union countries to be €50 million, excluding HCV drug therapy and monitoring, thereby demonstrating that, even with no public health action, HCV causes significant costs to society. The predicted estimates for Spain were approximately €3 billion for the period 2010–2030, and in Canada the costs are estimated at CD$150 million annually until 2040. There is, therefore, an urgent economic and medical need for the development of an effective vaccine against hepatitis C. The present treatment of hepatitis C infection consists of a combination of peginterferon and ribavirin, and on this treatment viral eradication can be achieved in only half of all of the patients with HCV genotype 1 and in ≥90% of patients with HCV genotype 2 or 3. Treatment may take 6 to 18 months and therapy-associated adverse effects such as pancytopenia, flu-like symptoms, or depression are common and may lead to early discontinuation of drugs and treatment failure (10). Recent improved understanding of the HCV life cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets; however, viral entry and fusion, RNA translation, virus assembly and release, and several host cell factors may provide alternative attractive targets for future anti-HCV drugs. Inhibitors of the HCV NS3/4A protease are presently in an advanced clinical development phase. Monotherapy with protease inhibitors has shown high antiviral activity, but it is associated with frequent selection of resistant HCV variants, often resulting in viral breakthrough; however, there is encouraging evidence, from phase 3 trials in adults, that the addition of a protease inhibitor (eg, telaprevir, boceprevir) to pegylated interferon-a/ribavirin substantially improves sustained virological response rates in both treatment-naïve and treatment-experienced patients with HCV genotype 1. Nucleotide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes, but seem to have a higher genetic barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for nonnucleoside inhibitors of the NS5B polymerase (11); however, the development of a substance with high antiviral activity and a high genetic barrier to resistance seems, so far, to be difficult. Among the different host cell–targeting compounds in early clinical development, cyclophilin inhibitors have shown the most promising results. Although advances have also been made in improving interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens. Further research is warranted in developing newer antiviral drugs, including multicentre trials, not only in adults but also in children. PLANS TO ACHIEVE THE GOALS Medical Intervention Goals Universal Hepatitis B Immunisation To start, high-endemicity areas need to be targeted for mass immunisation programs. The vaccine would be administered as part of a routine immunisation program, which can reach a large part of the population. For achieving this, there would need to be strong government support along with financial support from other funding agencies. Substantial resources are needed to support manufacturing and distribution of the vaccine. The vaccine, however, should be administered free of cost to the population. For implementation of universal immunisation of the vaccine, the general population will need to be educated about the vaccine. Printed and electronic communication should be used for spreading information about the vaccine and the immunisation programs. Women of child-bearing age and children should be especially targeted with a specific immunisation program. Multicentre International Trials on Safety and Efficacy of New Drugs for Treatment of CHB and CHC in Children Until recently, the only drugs used for treatment of hepatitis B were interferon and lamivudine, but now there are a number of studies under way on the potential use of newer antivirals, such as telbivudine and entecavir, in the paediatric population. The results of these studies have been encouraging with regard to their safety and efficacy, although the Food and Drug Administration has still not given approval for their use in children. The only drugs approved for use in children are lamivudine and interferon. Adefovir was recently approved for use in children older than 12 years. There is a need for further development of new, effective therapies against hepatitis B and C. Large multicentre trials to validate the safety and efficacy of new drugs should be planned. International meetings, conferences, symposia CMEs, and so on are needed to generate new ideas and lead to planning of multicentre international trials on existing and new drugs for treatment of hepatitis B and C. These trials will require a large amount of funding, which should come from multiple sources such as governments, NGOs, WHO, UNICEF, the Bill and and the The progress of the trials and will need to be at the and of and for of HBV The guidelines available for CHB and CHC in children have been from There are only few drugs approved for use in children with adults. There are no universal guidelines to these diseases specifically in children. in adults, the guidelines are not although the for the of guidelines are most Knowledge about treatment of hepatitis B is and further need to generate evidence-based guidelines on management of children with HBV and HCV and, where evidence is large studies to future There should also be to these guidelines are worldwide. Research Goals of for HCV as has already been has many strains and mutates it difficult to target with a vaccine that is vaccine development approaches are therefore These vaccines that have been used for viral infections such as hepatitis B. HCV vaccine could of antibody and in a HCV In the of major in this than as recombinant or could that immune with effects on as that are within a vaccine or used as a vaccine a in the of that 3 and a of in the HCV region. In of this resulted in specific that specific antigen sites that were by cell system was and to These results suggest that the is and can both and immune In this is to which are for viral This may be significant for vaccine development and could be a to be in the of a and vaccine against of an for to HBV there is a vaccine for hepatitis B, which is a vaccine made of recombinant HBsAg. This is to generate a response but not a response. vaccines are made of which are to produce 1 or 2 specific antigen from and thus can lead to the of a of immune including response. These vaccines need to be developed and tested for those who do not develop response to the available vaccine. of Drugs and for HBV The treatment presently available for hepatitis B is mainly dependent on interferon and lamivudine, an immunomodulatory and antiviral The of both these drugs a depending on a number of vaccines are presently available for chronic viral such as human and an alternative to antiviral treatment or to support a treatment that is only a vaccine that would the immune system to and control or even the virus is whereas the present success of vaccination is on of the by virus control and of infected require of a and response against viral is a of vaccination and also of a immune response to virus with multicentre clinical trials on newer antiviral therapies ideas of using vaccine as treatment should be Education Goals Public Awareness of and Prevention of Hepatitis B Public awareness programs should be on a These should and electronic There should be on the transmission and prevention of hepatitis B and C infection and there should be on the should also be in and areas to educate the public and about the disease. and should also be used to the public should spread general awareness to the The NGOs, and international funding should support the by financial required for the implementation of programs. of on and for Children CHB and Hepatitis C To implementation and of the guidelines for management of hepatitis B and C, there should be programs for paediatricians and general on the should be to and should have free access to including in and The to antiviral therapy and the of drug are There is a risk of spreading resistance to a drug antiviral therapy is started a proper understanding of For this experts need to be in managing these cases. This will require general physicians to appropriate cases to where the are in the management of complicated cases of hepatitis B and C. This can be achieved by with these physicians and information on when and how to the cases. and the Public on and and Education to improve public knowledge and awareness of the of transmission including vertical transmission and prevention of HBV and HCV infection is The rate of HBV infection to infants is higher the has acute hepatitis in the as with in The of is to HBV vertical transmission and There are studies that the combination of and HBV is a of vertical transmission than is higher in infants by route than by This can be by a risk of during to a higher risk of transmission of hepatitis C infection, but this effect by improving with treatment. does not increase the in exclusive can be protective against the disease. There is a low viral in there is by and has proven immunological Public education and putting this knowledge by the public is extremely important. In hepatitis B and C are major that affect the health of children of the but with major in and countries. The of priorities and of medical interventions, and education may and policy to promote that would improve the and of of children.

There is a general consensus that during chronic Trypanosoma cruzi infection, the host immune system induces complex processes to ensure the control of parasite growth while preserving the potential to mount and maintain a life-long controlled humoral and cellular immune response against the invading pathogen. This review summarises evidence in an attempt to elucidate 'what must be understood' to further clarify the role of innate immunity in the development/maintenance of clinical Chagas disease and the impact of etiological treatment on host immunity, highlighting the contributions of the innate immunity and regulatory T (Treg) cells. Recently, increasing focus on innate immunity suggest that chronic T. cruzi infection may cause morbidity when innate effector functions, or the down-regulation of adaptive regulatory mechanisms are lacking. In this context, stable asymptomatic host-parasite interactions seem to be influenced by the effector/regulatory balance with the participation of macrophages, natural killer (NK) and CD8+ T cells in parallel with the establishment of regulatory mechanisms mediated by NKT and Treg cells. Moreover, a balanced innate immune activation state, apart from Treg cells, may play a role in controlling the adverse events triggered by the massive antigen release induced by trypanosomicidal agents during Chagas disease etiological treatment.

Described by the Brazilian scientist Carlos Chagas more than a century ago, Chagas disease (ChD) currently affects 8 to 10 million persons and causes more than 10 000 deaths each year.[1][1] Originally confined to Latin American countries, ChD had been considered an exotic disease and received less

BackgroundRare diseases have been increasingly recognized as unmet medical and health needs worldwide; a growing demand for the development of orphan drugs emerges subsequently. Therefore, it is of great interest for both the Chinese regulatory agency and pharmaceutical companies to keep tract on the clinical development of orphan drugs in China.Objective and methodThis study aims to reveal the current situation and trend of the clinical development of orphan drugs in China, based on the data collected from the Chinese official platform, dating from January 1, 2013 to December 31, 2021.ResultsA total of 331 clinical trials for orphan drugs were extracted from the platform, covering 31 rare diseases and 124 drugs. Increases were seen in the annual number of clinical trials and drugs being tested, with a sharp increase after 2018. About the disease types of the 331 trials, Parkinson disease (young-onset, early-onset) (86, 26%), hemophilia (70, 21%), homozygote hypercholesterolemia (60, 18%) were the most common. Furthermore, it was also observed that the largest number of clinical trial units for rare disease in east China (90, 41%) and the smallest number located in northwest China (18, 6%) and northeast China (18, 6%).ConclusionsThe growth trends illustrate the progress in clinical trial and drug development of rare diseases from 2013 to 2021. However, promoting orphan drugs development still is an important issue in China; at the same time, further efforts should be made for meet the unmet needs of disease types and balance the uneven distribution of medical resources for clinical trial on rare diseases.

The paleopathological, paleoradiological, histological, molecular and forensic investigation of a female mummy (radiocarbon dated 1451–1642 AD) provides circumstantial evidence for massive skull trauma affecting a young adult female individual shortly before death along with chronic infection by Trypanosoma cruzi (Chagas disease). The mummy (initially assumed to be a German bog body) was localized by stable isotope analysis to South America at/near the Peruvian/Northern Chilean coast line. This is further supported by New World camelid fibers attached to her plaits, typical Inca-type skull deformation and the type of Wormian bone at her occiput. Despite an only small transverse wound of the supraorbital region computed tomography scans show an almost complete destruction of face and frontal skull bones with terrace-like margins, but without evidence for tissue reaction. The type of destruction indicates massive blunt force applied to the center of the face. Stable isotope analysis indicates South American origin: Nitrogen and hydrogen isotope patterns indicate an extraordinarily high marine diet along with C4-plant alimentation which fits best to the coastal area of Pacific South America. A hair strand over the last ten months of her life indicates a shift to a more “terrestric” nutrition pattern suggesting either a move from the coast or a change in her nutrition. Paleoradiology further shows extensive hypertrophy of the heart muscle and a distended large bowel/rectum. Histologically, in the rectum wall massive fibrosis alternates with residual smooth muscle. The latter contains multiple inclusions of small intracellular parasites as confirmed by immunohistochemical and molecular ancient DNA analysis to represent a chronic Trypanosoma cruzi infection. This case shows a unique paleopathological setting with massive blunt force trauma to the skull nurturing the hypothesis of a ritual homicide as previously described in South American mummies in an individual that suffered from severe chronic Chagas disease.