Tracing the path of Chikungunya virus—Evolution and adaptation

An epidemic of dengue haemorrhagic fever occurred in Delhi during 1988. A total of 21 paediatric patients with dengue haemorrhagic fever/dengue shock syndrome were evaluated from September to November 1988. All the patients had fever, restlessness, ecchymotic spots and ascites. Pleural effusion occurred in 19 patients (90%), and 18 (86%) exhibited each of the following: vomiting, thrombocytopenia, and haemoconcentration. Hepatomegaly was observed in 15 patients (71%) and splenomegaly in three (14%). Titres of haemagglutination inhibition (HI) antibodies against dengue virus type 2 were raised in all the 15 cases from whom sera were collected during the acute stage. Convalescent sera from five patients had increased titres of HI antibodies to dengue virus type 2. The remaining 10 cases exhibited raised IgM antibody levels against dengue virus type 2. The fatality rate for serologically proven cases was 13% (2 of 15 patients), while for all patients (including those diagnosed clinically (6) and serologically (15)) it was 33.3% (7 of 21). Patients who survived had no sequelae, except one who had transient hypertension that lasted for two weeks.

Dengue haemorrhagic fever in children in Delhi.

BACKGROUND Postexposure vaccination strategies rely on a rapid induction of poxvirus-specific immune responses. Postvaccination cell-mediated immune (CMI) responses have not been compared by use of controlled trials in previously vaccinated (vaccinia-nonnaive) and nonvaccinated (vaccinia-naive) individuals. METHODS To assess the time course of vaccinia-specific CMI responses, 20 previously vaccinated and 10 vaccinia-naive individuals were vaccinated with Dryvax, and serial blood samples were drawn. RESULTS Both groups developed peak levels of vaccinia-specific interferon (IFN)- gamma -producing T cells by day 14 after vaccination. In vaccinia-nonnaive individuals, vaccinia-specific CMI responses were detected by day 7 after vaccination and preceded the increase in antibody titers. IFN- gamma enzyme-linked immunospot responses were significantly different between the 2 groups on days 7 (greater in vaccinia-nonnaive than in vaccinia-naive individuals) and 14 (greater in vaccinia-naive than in vaccinia-nonnaive individuals). Lymphoproliferation responses in vaccinia-nonnaive individuals were significantly higher on days 3 and 7, but cytotoxic T cell lysis activity was not statistically different at any time point. Antibody responses conformed to expected primary and secondary patterns of induction. CONCLUSIONS This study demonstrates that the kinetics of CMI responses are different after primary vaccination versus after revaccination and indicates that memory can exist in individuals vaccinated >/=30 years ago. These data support the epidemiological observation in smallpox outbreaks that successful revaccination within 4 days of exposure is partially protective. In vaccinia-nonnaive individuals, protection against smallpox during the postexposure revaccination period may require T cell memory as an essential component for the rapid induction of protective cellular and humoral responses.

Induction of Human T Cell-Mediated Immune Responses after Primary and Secondary Smallpox Vaccination

Technological innovation and rapid reduction in sequencing costs have enabled the genomic profiling of hundreds of cancer-associated genes as a component of routine cancer care. Tumour genomic profiling can refine cancer subtype classification, identify which patients are most likely to benefit from systemic therapies and screen for germline variants that influence heritable cancer risk. Here, we discuss ongoing efforts to enhance the clinical utility of tumour genomic profiling by integrating tumour and germline analyses, characterizing allelic context and identifying mutational signatures that influence therapy response. We also discuss the potential clinical utility of more comprehensive whole-genome and whole-transcriptome sequencing and ultra-sensitive cell-free DNA profiling platforms, which allow for minimally invasive, serial analyses of tumour-derived DNA in blood.

Clinical cancer genomic profiling.

IFN function is critical for recovery from most primary viral infections, including poxvirus infection. In contrast, very little is known about the requirement for IFN function in mediating recovery from a secondary virus infection. We have used ectromelia virus (ECTV), an orthopoxvirus very closely related to variola virus, to investigate the importance of IFN function in recovery from a secondary infection. Variola virus, the causative agent of smallpox in humans, and ECTV, which causes mousepox in mice, both encode receptor homologs that are thought to interfere with host IFN function. Using a prime-challenge regime, in which avirulent ECTV is used to prime mice deficient in type I/II IFN function or IFN regulatory factor 1 (IRF-1) and then challenging the mice with a virulent strain, we show that IFN function is redundant for virus clearance during a secondary ECTV infection. A neutralizing Ab response is generated in a secondary infection, even in the absence of IFN function, although when present, IFN strongly influences the neutralizing titer and subtype of IgG that is produced. Importantly, the depletion of CD8+ T lymphocytes during a secondary challenge in IFN-deficient mice does not affect their capacity to clear ECTV, indicating that Ab is critical for the control of a secondary infection.

Interferon function is not required for recovery from a secondary poxvirus infection

A new type of fever characterized by haemorrhagic manifestations or shock or both broke out in Calcutta as a double-peak epidemic in 1963. The epidemic was almost as severe in 1964 as in 1963, but in 1965 the morbidity was much less. 302 cases diagnosed clinically as haemorrhagic fever were virologically and serologically investigated during this period. 55% had arthralgia, 18% had skin rash, 14% had lymphadenitis and 28% had frank haemorrhage. Chikungunya virus, apparently a new one in India, was isolated from 64 patients and dengue virus (3 type 2, 2 type 4, and one probably type 1) from 6. In addition to those, a number of cases were diagnosed serologically as either chikungunya or Group B arbovirus (probably dengue) infection. In many of the cases with severe haemorrhagic manifestations or shock, dengue virus aetiology could be established, and in some, chikungunya aetiology without any evidence of simultaneous dengue infection could be shown. 10 of the 302 patients died. 18·8% of 439 human sera collected in 1964 and 32·3% of 537 sera collected in 1965 were positive against chikungunya antigen by the HI test. 14% of sera collected in Calcutta during 1960 were also positive by this test, indicating that chikungunya or a similar virus was present in the country before the outbreak of haemorrhagic fever in 1963. Chikungunya virus was isolated from 2 of 15 pools of Aedes aegypti (total 464). Laboratory-bred Aedes aegypti fed on acute chikungunya fever cases were found capable of transmitting the infection to infant mice.

Three-year study of mosquito-borne haemorrhagic fever in Calcutta

Dengue haemorrhagic fever (DHF) usually occurs in epidemic form. Whilst investigating two epidemics of classical dengue, 8 sporadic cases with haemorrhage and/or shock were encountered. Although dengue virus was not isolated from them, results of examination of paired sera of 2 of them and acute sera of others by haemagglutination-inhibition and complement fixation tests against group A and group B arbovirus antigens suggest that the illness was the result of dengue virus infection. The importance of bearing in mind the possibility of sporadic cases of DHF is stressed.

Sporadic cases of haemorrhage and/or shock during dengue epidemics

Data of 170 smallpox cases have been analysed to find the relationships between clinical severity, level of haemagglutination-inhibiting (H.I.) antibody and vaccination state. Only primary vaccination, irrespective of its timing was taken into account. That previous vaccination has a salutary effect on the severity of the disease was evident from the fact that all the haemorrhagic patients were unvaccinated, but the vaccination state could not explain the proportion of confluent and discrete cases. The differences in the mean antibody titres between the vaccinated and unvaccinated sets were not significant in both the confluent and discrete groups, but the confluent group, as a whole had a higher antibody response than the discrete group.

J.K. Sarkar

Papers

Three-year study of mosquito-borne haemorrhagic fever in Calcutta

Sporadic cases of haemorrhage and/or shock during dengue epidemics

Relationship of clinical severity, antibody level, and previous vaccination state in smallpox.

A tissue culture model for testing anti-microfilarial drugs