An analytical review of vector- and pathogen-based transmission-blocking vaccine for malaria control

Malaria is a vector borne disease, considered to be one of the most serious public health problems. The present review focused on the blocking of parasite development in mosquito vectors; one broad strategy for achieving this is Transmission Blocking Vaccines (TBV). The TBVs usually rely on immunization of vertebrate hosts with molecules derived from the vector or pathogen to reduce pathogen transmission from infected to uninfected hosts. Most of the studies on the TBVs are based on the antibodies targeted against the surface antigens of sexual stages of malaria parasite, but it is meagre to develop mosquito-based vaccine in this regard. Vector-based TBVs include surface proteins that are expressed by the mosquito midgut digestive enzymes which are induced upon blood-feeding, and receptors expressed on the epithelial line of the tissue. Many proteins are reported that can act as candidates for transmission-blocking vaccines. This review aims to summarize the vector midgut-based proteins identified till date, that can block the development and maturity of sexual stages of the parasite within mosquitoes as targets for transmission-blocking vaccine development. The TBVs intervention can block transmission of different malaria parasite species in various species of mosquitoes with future application perspective worldwide.

Epidemiological characteristics and interruption of 228 HBV positive pregnant women / 公共卫生与预防医学

Objective To investigate the epidemiological characteristics and interruption of 228 hepatitis B virus (HBV) positive pregnant women, and to provide more references for clinical education and treatment. Methods A total of 228 chronic HBV pregnant women underwent maternal-neonatal transmission blocking treatment in Third Affiliated Hospital of Sun Yat-sen University from January 2015 to April 2019 were enrolled. Self-designed follow-up questionnaires were used to collect pregnant women's data. Then the relationship of epidemiological characteristics and HBV-DNA load levels with the genotype, hepatitis B e antigen (HBeAg), and alanine aminotransferase (ALT) was analyzed, moreover, the prevention of mother-to-child transmission was also analyzed. Results A total of 228 HBV-positive pregnant women were mainly over 30 years old, with a family history of liver disease, low education level (

Surveillance of schistosomiasis in People's Republic of China in 2015 / 中国血吸虫病防治杂志

Objective To analyze the investigation data of the national schistosomiasis surveillance sites in 2015,so as to provide scientific evidences for schistosomiasis control,elimination and surveillance. Methods According to National Schisto-somiasis Surveillance Programme(version 2014),457 surveillance sites were selected,and the investigation data in residents, floating population,domestic animals and Oncomelania hupensis snails were collected and analyzed from four types of endemic counties. Results A total of 4468 seropositive cases were detected from 133350 residents,among which 4457 residents with seropositive results received the etiological tests,and 71 of them were identified with positive results. Most of them were fisher-men and farmers in the middle and old-aged group. The schistosomiasis infection rate was 0.05% in local population. Totally 977 seropositive cases were examined from 85047 migrant individuals,and 16 positive cases were found out from 966 individuals who took etiological tests,which showed the schistosomiasis infection rate was 0.02% in floating population. Imported cases were found among floating people in four provinces,namely Zhejiang,Hunan,Hubei and Anhui provinces. No acute schistoso-miasis cases were reported. A total of 13406 head of cattle received examinations and only 5 were determined as stool positives. The cattle infection rate was 0.04%. The snail survey covered an area of 22295.13 hm2 and snails were found in an area of 7426.63 hm2,including 3.47 hm2 newly detected area with snails. No schistosome-infected snails were found. Conclusions Based on the collected data from 457 national schistosomiasis surveillance sites of China,the Schistosoma japonicum infection rate is 0.05% in local population which maintains a stably descending trend. In floating population,there are imported schistosome-in-fected persons. Cattle are still a vulnerable species infected with schistosome. Although no infected snails are found,snails are widely distributed in endemic areas. Some provinces detect areas with snails for the first time or the reproduction of snails. The staff in endemic provinces should carry out the surveillance work according to National Schistosomiasis Surveillance Programme (version2014)to improve the surveillance system,and enhance the sensibility and effectiveness of surveillance work.

Blocking efficacy of 23 cases of mother to child transmission of acquired immunodeficiency syndrome in the First Hospital of Changsha / 中国感染控制杂志

Objective To observe the blocking efficacy of mother to child transmission (MTCT) in pregnant women with positive human immunodeficiency virus(HIV), and explore proper MTCT blocking mode for acquired immunodeficiency syndrome.Methods Clinical data of 23 HIV-positive pregnant women in a hospital from 2005 to 2015 were retrospectively analyzed.Results All 23 HIV-positive pregnant women received highly active antiretroviral therapy (HAART) and comprehensive intervention for blocking MTCT of HIV.Among these women, 12 got pregnant after receiving HAART, 10 were detected positive HIV in early pregnancy (within 28 weeks) and then received HAART, 1 was detected positive HIV 28 weeks after pregnancy and then received HAART.23 HIV-positive pregnant women all delivered normal newborns, follow-up observation of babies found no HIV infection.Conclusion HAART for HIV-positive pregnant women is the key to block MTCT of HIV, combined with preventive medication and artificial feeding of newborns, HAART can effectively prevent MTCT.Mutual blocking mode, such as HAART for HIV-positive pregnant women by specialists, pregnancy check-up, and preventive medicine for infants provided by maternity and child care hospital, is highly efficiency.

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum.

Transmission blocking malaria vaccines are aimed to block the development and maturity of sexual stages of parasite within mosquitoes. The vaccine candidate antigens (Pfs25, Pfs48/45, Pfs230) that have shown transmission blocking immunity in model systems are in different stages of development. These antigens are immunogenic with limited genetic diversity. Pfs25 is a leading candidate and currently in phase I clinical trial. Efforts are now focused on the cost-effective production of potent antigens using safe adjuvants and optimization of vaccine delivery system that are capable of inducing strong immune responses. This review addresses the potential usefulness, development strategies, challenges, clinical trials and current status of Plasmodium falciparum sexual stage malaria vaccine candidate antigens for the development of transmission-blocking vaccines.

Cloning,expression and identification of gametocyte specific protein Pfgdv1 of Plasmodium falciparum / 中国血吸虫病防治杂志

Objective To clone a gametocyte specific protein Pfgdv1 of Plasmodium falciparum,express and identify re?combinant Pfgdv1 protein in vitro. Methods PCR was performed to amplify Pfgdv1 from P. falciparum DNA which was got from the patient who was infected with P. falciparum,and the PCR product was inserted into pET28a(+)vector. pET28a?Pfg?dv1 recombinant plasmid was constructed and transformed into E. coli host BL21(DE3+). IPTG was used to induce the recombi?nant Pfgdv1 protein fused with His tag,and the protein was purified by His?NTA affinity chromatography. The recombinant pro?tein was identified by SDS?PAGE and Western blotting. Results The PCR product of Pfgdv1 gene was about 1.65 kb,meeting the expectation of predicted fragment size. The recombinant protein was about 67 kDa,which could be recognized by His?Tag monoclonal antibody. Conclusion The Pfgdv1 gene of P. falciparum is successfully cloned,and the recombinant Pfgdv1 pro?tein is expressed,thereby providing an opportunity for further study on transmission blocking vaccine.

Sequence polymorphisms in Pvs48/45 and Pvs47 gametocyte and gamete surface proteins in Plasmodium vivax isolated in Korea

Nucleotide sequence analyses of the Pvs48/45 and Pvs47 genes were conducted in 46 malaria patients from the Republic of Korea (ROK) (n = 40) and returning travellers from India (n = 3) and Indonesia (n = 3). The domain structures, which were based on cysteine residue position and secondary protein structure, were similar between Plasmodium vivax (Pvs48/45 and Pvs47) and Plasmodium falciparum (Pfs48/45 and Pfs47). In comparison to the Sal-1 reference strain (Pvs48/45, PVX_083235 and Pvs47, PVX_083240), Korean isolates revealed seven polymorphisms (E35K, H211N, K250N, D335Y, A376T, I380T and K418R) in Pvs48/45. These isolates could be divided into five haplotypes with the two major types having frequencies of 47.5% and 20%, respectivelfy. In Pvs47, 10 polymorphisms (F22L, F24L, K27E, D31N, V230I, M233I, E240D, I262T, I273M and A373V) were found and they could be divided into four haplotypes with one major type having a frequency of 75%. The Pvs48/45 isolates from India showed a unique amino acid substitution site (K26R). Compared to the Sal-1 and ROK isolates, the Pvs47 isolates from travellers returning from India and Indonesia had amino acid substitutions (S57T and I262K). The current data may contribute to the development of the malaria transmission-blocking vaccine in future clinical trials.

Primaquina, gametocitemia de Plasmodium falciparum y bloqueo de transmisión: ineficacia del actual régimen de dosificación / Primaquine, Plasmodium falciparum gameto cytemia and blocking transmission: inefficiency of the current dosing scheme

Antecedentes: Los esquizonticidas anti-Plasmodium falciparum reducen la gametocitemia, sin erradicarla; por ello, se adiciona primaquina (PQ). Esta se administra al terminar el esquizonticida: día 4; 0,75 mg/kg; dosis única (régimen estándar). Las artemisininas actúan sobre gametocitos inmaduros I-IV de P. falciparum; la PQ actúa (stages I-IV) of P. falciparum; PQ acts on mature sobre gametocitos maduros (estadio V). ¿Cuál es la eficacia antigametocitos de la combinación esquizonticida-PQ? Objetivo: Analizar la eficacia de PQ-régimen estándar contra gametocitos de P. falciparum, asociada al esquizonticida. Metodología:Revisión sistemática de los artículos hallados en Pubmed y Lilacs. Resultados y conclusiones: Ningún esquizonticida elimina totalmente los gametocitos en 6-7 días iniciales de tratamiento. La adición de PQ-régimen estándar tiene potente acción antigametocitos. Ninguna combinación esquizonticida-PQ tiene eficacia total en ese plazo. No conocemos cómo varía la eficacia antigametocitos de PQ dada los días 1 a 3, ni en dosis diferentes a la estándar, ni en múltiples dosis. [Carmona-Fonseca J, Arango EM. Primaquina, gametocitemia de Plasmodium falciparum y bloqueo de transmisión: ineficacia del actual régimen de dosificación. the current dosing scheme. MedUNAB 2012; 15:14-21].

Background: Anti-Plasmodium falciparum schizontocides decrease gametocytemia, not eliminate it; by this, he added primaquine (PQ). The PQ is administered after the treatment schizonticide: day 4; 0.75 mg/kg single dose (standard regimen). The artemisinins act on immature gametocytes (stages I-IV) of P. falciparum; PQ acts on mature gametocytes (stage V). What is the efficacy of the combination schizontocide-PQ against gametocytes? Objective: Analyze the effectiveness of PQ-standard regimen against gametocytes of P. falciparum, associated with schizonticide. Methodology: Systematic review of articles found in PubMed and Lilacs. Results and conclusions: No schizonticide completely eliminates the gametocytes in initial treatment 6-7 days. The addition of PQ-standard regimen has potent anti-gametocytes. No combination has efficacy schizonticide-PQ total in that period. We do not know how the efficiency varies anti-gametocytes of PQ given on days 1 to 3, or different from the standard dose or multiple doses. [Carmona-Fonseca J, Arango EM. Primaquine, Plasmodium falciparum gametocytemia and blocking transmission: inefficiency of the current dosing scheme. MedUNAB 2012; 15:14-21].

Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin America

Malaria is a vector-borne disease that is considered to be one of the most serious public health problems due to its high global mortality and morbidity rates. Although multiple strategies for controlling malaria have been used, many have had limited impact due to the appearance and rapid dissemination of mosquito resistance to insecticides, parasite resistance to multiple antimalarial drug, and the lack of sustainability. Individuals in endemic areas that have been permanently exposed to the parasite develop specific immune responses capable of diminishing parasite burden and the clinical manifestations of the disease, including blocking of parasite transmission to the mosquito vector. This is referred to as transmission blocking (TB) immunity (TBI) and is mediated by specific antibodies and other factors ingested during the blood meal that inhibit parasite development in the mosquito. These antibodies recognize proteins expressed on either gametocytes or parasite stages that develop in the mosquito midgut and are considered to be potential malaria vaccine candidates. Although these candidates, collectively called TB vaccines (TBV), would not directly stop malaria from infecting individuals, but would stop transmission from infected person to non-infected person. Here, we review the progress that has been achieved in TBI studies and the development of TBV and we highlight their potential usefulness in areas of low endemicity such as Latin America.

Effect of anti-fat body antibodies on reproductive capacity of mosquito Anopheles stephensi and transmission blocking of Plasmodium vivax.

Effect of anti-mosquito-fat body antibodies on the development of the malaria parasite, Plasmodium vivax has been studied by feeding Anopheles stephensi mosquitoes with infected blood supplemented with serum from immunized rabbits. Immunogenic polypeptides were identified by western blot. Mosquitoes that ingested anti-fat body antibodies along with infectious blood meal had significantly fewer oocysts than the mosquitoes in the control group. Effect of anti-mosquito fat body antibodies on fecundity, hatchability, mortality and engorgement of mosquitoes has also been reported. A significant reduction in fecundity and hatchability was observed, however, effect on mortality and engorgement was variable and statistically insignificant. Results indicated that fat body antibodies have the potential to disrupt reproductive physiology of malaria vector An. stephensi.

Transmission blocking vaccines to control insect-borne diseases: a review

Insect-borne diseases are responsible for severe mortality and morbidity worldwide. As control of insect vector populations relies primarily on the use of insecticides, the emergence of insecticide resistance as well to unintended consequences of insecticide use pose significant challenges to their continued application. Novel approaches to reduce pathogen transmission by disease vectors are been attempted, including transmission-blocking vaccines (TBVs) thought to be a feasible strategy to reduce pathogen burden in endemic areas. TBVs aim at preventing the transmission of pathogens from infected to uninfected vertebrate host by targeting molecule(s) expressed on the surface of pathogens during their developmental phase within the insect vector or by targeting molecules expressed by the vectors. For pathogen-based molecules, the majority of the TBV candidates selected as well as most of the data available regarding the effectiveness of this approach come from studies using malaria parasites. However, TBV candidates also have been identified from midgut tissues of mosquitoes and sand flies. In spite of the successes achieved in the potential application of TBVs against insect-borne diseases, many significant barriers remain. In this review, many of the TBV strategies against insect-borne pathogens and their respective ramification with regards to the immune response of the vertebrate host are discussed.

Appropriate Time for Primaquine Treatment to Reduce Plasmodium falciparum Transmission in Hypoendemic Areas

Artemesinin-combination therapies (ACT) for falciparum malaria reduce gametocyte carriage, and therefore reduce transmission. Artemisinin derivatives will act against only young gametocytes whereas primaquine acts on mature gametocytes which are present usually in the circulation at the time when the patient presents for treatment. Both artemisinin derivatives and primaquine have short half-lives, less than 1 hr and 7 hr, respectively. Therefore, asexual parasites or young gametocytes remain after completed ACT. A single dose of primaquine (0.50-0.75 mg base/kg) at the end of ACT can kill only mature gametocytes but cannot kill young gametocytes (if present). Remaining asexual forms after completion of ACT course, e.g., artesunate-mefloquine for 3 days, may develop to mature gametocytes 7-15 days later. Thus, an additional dose of primaquine (0.50-0.75 mg base/kg) given 2 weeks after ACT completion may be beneficial for killing remaining mature gametocytes and contribute to more interruption of Plasmodium falciparum transmission than giving only 1 single dose of primaquine just after completing ACT.

Transgenic mosquitoes for malaria control: progresses and challenges / Mosquitos transgênicos para o controle da malária: progressos e desafios

Malaria kills millions of people every year and the current strategies to control the disease, such as insecticides and drugs have not been completely efficient. Because of that, novel means to fight against malaria are of utmost importance. Advances in the study of the mosquito vector and its interactions with the malaria parasite made scientists think that it is possible to genetically manipulate the mosquitoes to make them inefficient vectors. Here we review the advances on the introduction of foreign genes into the mosquito germ line, the characterization of tissue-specific promoters, the identification of gene products that block development of the parasite in the mosquito, and we discuss the recent generation of transgenic mosquitoes impaired for malaria transmission. While much progress has been made, many years of research are still needed before transgenic mosquitoes can be used in the field.

A malária mata milhões de pessoas a cada ano e as estratégias atuais de controle da doença, como inseticidas e drogas não têm sido tão eficientes. Por este motivo, novos meios para o combate à malária são de extrema importância. Avanços no estudo do mosquito vetor e sua interação com o parasito da malária fizeram os cientistas pensarem que é possível a manipulação genética dos mosquitos para torná-los vetores ineficientes. Neste artigo, revisamos os avanços na introdução de genes exógenos na linhagem germinativa de mosquitos, a caracterização de promotores específicos de certos tecidos, a identificação de produtos gênicos que bloqueiam o parasita no mosquito, bem como discutimos a recente geração de mosquitos transgênicos, menos eficientes na transmissão de malária. Enquanto muitos progressos foram obtidos, muitos anos de pesquisa são ainda necessários para que mosquitos transgênicos possam ser utilizados na natureza.

Transmission-blocking Vaccine Candidate of Plasmodium vivax Pvs25 Is Highly Conservative among Chinese Isolates / 中国寄生虫学与寄生虫病杂志

Objective To investigate the genetic diversity of Plasmodium vivax transmission_blocking vaccine candidate antigen (TBV) Pvs25, with P.vivax isolates from Hubei and Zhejiang Provinces, and to compare the genetic polymorphism of Pvs25 with that from Bangladesh. MethodsThe parasite DNA used for the genetic polymorphism assay was obtained from dried filter paper blood spots. The genes were PCR amplified and the products were purified and sequenced directly. Results 45 complete new sequences were analyzed. Only 3 nucleotide changes were found that would result in amino acid substitutions in Pvs25 in comparison with the sequence from P.vivax Sal_I strain. The measurement of nucleotide diversity (?) was remarkably similar for the two populations, indicating that DNA sequences and deduced amino acid sequences were highly homologous among the geographically dispersed isolates or isolates from the same geographical region.Conclusion The results suggest that Pvs25 has limited antigenic polymorphism, especially compared with candidate antigens expressed by hepatic and erythrocytic stage, which may support the development and application of Pvs25_based transmission_blocking vaccine in China.

In vitro Observation on Effect of Nitric Oxide on Exflagellation of Plasmodium yoelii / 中国寄生虫学与寄生虫病杂志

Objective To observe the effect of nitric oxide (NO) on exflagellation of malaria parasite. Methods The level of parasitemia and gametocytemia in DBA/2 mice infected with Plasmodium yoelii 17XL was measured by scanning Giemsa-stained blood smears, and the NO level in culture supernatant of splenocytes was checked using Griess reaction. The mice were injected with different doses of NO donor (NOC5) on day 4 post-infection, and control mice were injected with NOC5 precursor. On day 6 post-infection, mice were injected with NOS inhibitor (L-NMMA), and control mice were injected with D-NMMA and PBS, respectively. Blood samples were collected from tail vein of mice before injection, 30 and 60 min after being injected with NOC5 and NOC5 precursor, 4 and 8 h after being injected with L-NMMA, D-NMMA, and PBS respectively. Exflagellation number of gametocytes in blood culture was counted under microscope. Results The NO level in culture supernatant of splenocytes from mice on day 4 and 6 post-infection was 16.5 mmol/L and 30.4 mmol/L, and exflagellation number was 11.33 and 0.66, respectively. The number of exflagellation in parasitized erythrocytes, obtained from mice on day 4 post-infection, was 5.33 and 2.66, respectively, 30 and 60 min after injection of 1 mg NO donor (NOC5), significantly lower than that of the control (P

Studies on the expression of Pys25 and Pys21 of Plasmodium yoelii and transmission blocking immunity / 中国免疫学杂志

Objective:To investigate the expression of antigens in Plasmodium yoelii sexual stage and transmission blocking effects of monoclonal antibodies(McAbs).Methods:Observing the effects of anti Pys25 McAb4 and anti Pys21 McAb10 on developmental course of parasites in mosquitoes by direct mosquito feeds on passively immunized P.yoelii infected mice and the expression of Pys21 and Pys25 from gametocytes to ookinetes in indicated culture times by IFA and Western blotting.Results:The transmission blocking activity of the anti Pys25 McAb4 was complete and more potent than that of the anti Pys21 McAb10.Both Pys25 and Pys21 were presented in whole developmental course from gametocytes to ookinetes.Furthermore,the expression of Pys25 appeared to be earlier than that of Pys21 on zygote surfact.Conclusion:Pys25 and Pys21 are target antigens of transmission blocking immunity and that anti Pys25 McAb4 has more significantly transmission blocking activity is related with the early stage expression of Pys25 on zygote surface.

Malaria vaccine: current status and perspective / 第二军医大学学报

The emergency and rapid spread of drug resistant parasites and mosquitoes resistant to insecticides urgently demand new tools to control the disease. It is feasible to develop malaria vaccine based on animal and volunteers test. Scientists around the world are working on 3 types of malaria vaccine——pre erythrocytic, blood stage and transmission blocking. Some of the vaccine candidates are being tested in clinical trials and have been shown to be promising. It is very difficult to find a successful malaria vaccine due to its complex life cycle, antigen variations and multiple invasion pathways, but the vaccine will finally be developed.