A phase I clinical trial of a multi-epitope polypeptide TAB9 combined with Montanide ISA 720 adjuvant in non-HIV-1 infected human volunteers.

A phase I clinical trial was performed to examine the safety and immunogenicity of a multi-epitope polypeptide comprising the central 15 amino acids of the V3 loop from six HIV-1 isolates. This protein called TAB9 was emulsified in Montanide ISA720 (Seppic, Paris) and administered intramuscularly at doses of 0, 0.2 and 1 mg to 24 healthy, HIV-1 seronegative adult males. Three immunisations were given at months 0, 1 and 6 in a randomised, double blind, placebo controlled clinical trial. The placebo was generally well tolerated. However, severe local reactions were observed in TAB9 vaccinated subjects after the second and third inoculations. Seven out of eight volunteers from the lower dose group showed moderate or severe local inflammation, while four out of eight subjects from the higher dose group developed granulomas and sterile abscesses. In general, the reactogenicity depended on the number of inoculations given and the dose of TAB9. Both doses were immunogenic, all immunised volunteers seroconverted and antibodies were broadly reactive against the V3 peptides included in the protein. All vaccine's sera reacted against gp120 in Western blot and 50% of them also neutralised at least one out of five laboratory isolates tested. No differences between doses were found. Anti TAB9 lymphoproliferative responses were observed, being more intense in the high dose group. Due to the strong local reactions that were found in this study, a change in the formulation will be required for further trials with this vaccine candidate in humans.

Isolates from four different HIV type 1 clades circulating in Cuba identified by DNA sequence of the C2-V3 region.

According to the epidemiology of human immunodeficiency virus infection in Cuba, the main sources of infection have been persons coming from foreign countries, mainly from Africa, and individuals who have had sexual contacts with foreigners in Cuba. However, the first Cuban HIV-1 isolates sequenced have been all classified as subtype B. In this note we report the sequence of the gp120 C2/V3 region from 11 HIV-1 isolates from Cuban patients. DNA was isolated either directly from blood PBMC or from primary isolates, PCR amplified and sequenced. Six isolates were classified as subtype B and three of them had the atypical sequences GRGR, GWGR, and TPGR on the tip of the V3 loop. Besides, two other sequences were classified as subtype A, two as subtype H, and one as subtype C. These results confirm that although subtype B seems to be predominant, HIV-1 isolates from various subtypes do circulate in Cuba.

The V3 loop based multi-epitope polypeptide TAB9 adjuvated with montanide ISA720 is highly immunogenic in nonhuman primates and induces neutralizing antibodies against five HIV-1 isolates.

In a previous work we selected montanide ISA720 (M-ISA720) among different adjuvants for the vaccination with a V3 loop based multi-epitope polypeptide TAB9. In this paper we present the evaluation of the toxicity and immunogenicity of this formulation in non-human primates. TAB9 in M-ISA720 was highly immunogenic in macaques (Macaca fascicularis) inducing antibodies against TAB9 in all animals after one inoculation and a strong anamnestic response after booster injections. Furthermore 97% of the V3 peptides included were recognized by TAB9 sera. No differences between doses of 200 microg and 1 mg of TAB9 in M-ISA720 were observed after four immunizations. Neutralizing antibodies against five HIV-1 isolates were detected in most animals. Animals remain healthy throughout the study and did not show lesions at the inoculation site.

Broadly reactive antibodies against a gp120 V3 loop multi-epitope polypeptide neutralize different isolates of human immunodeficiency virus type 1 (HIV-1).

A gene encoding for a novel multi-epitope polypeptide (TAB4) was synthesized and expressed in Escherichia coli. The protein was composed of 15 amino acid fragments derived from the V3 loop of HIV-1 isolates MN, IIIB, RF, JY1, BRVA and LR150, joined by five-amino-acid linkers. Immunogenicity of TAB4 in rabbits was studied, and the antibody response against individual peptides investigated. TAB4 was shown to be immunogenic in Complete Freund's Adjuvant in a dose-dependent manner, and was able to elicit a humoral response against all V3 epitopes included on the protein. Sera from some of the animals were able to neutralize the replication of viral strain MN, and in one case IIIB, with moderate titers. Some sera also neutralized several Cuban clinical strains, isolated in peripheral blood mononuclear cells, after one round of amplification in MT4 cells.

Isolation and virological characterization of HIV-1 in Cuba. Relationship with the clinical status of the patients.

The objective of this paper is the isolation and biological characterization of HIV-1 from patients at different clinical status of the disease. Clinical, epidemiological and virological aspects of 54 infected people were studied. Isolate HIV-1 strains were characterized and classified in relation with replication kinetics and cellular tropism as well as syncytium inducing (SI), and non syncytium inducing (NSI) capacity. The biological phenotype of viral isolates was correlated with the clinical status of each patient. HIV was isolated from 92.8% AIDS patients and 46.1% asymptomatic seropositive patients, 12 out of 26 strains of AIDS patients were classified rapid high (RH) and SI, however 2 out of 12 strains of asymptomatic seropositive carriers were considered similar too. The percentage of recovered viral isolates correlates with the patient's clinical status, and the association existing between the isolate biological phenotype and the clinical status of the infection in most of the cases, but not in all was demonstrated.

Envelope V3 region sequences of Cuban HIV-1 isolates.

The origin of HIV-1 species, responsible for the AIDS epidemic in Cuba, is a subject that has been intensely debated. This study represents an initial attempt to shed light on this issue, through sequence analysis of the V3 regions of viruses isolated from 15 Cuban subjects. We now report that these viruses fall within three distinct, well-recognized groupings. These findings suggest that viruses of different sources are responsible for the HIV/AIDS epidemic in Cuba.

Cuadro clinico de la fiebre hemorragica del dengue/sindrome del choque del dengue en el adulto

Previous descriptions of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in adults have been limited. This article assesses the disease cases of 130 Cuban adults who became ill during the 1981 dengue epidemic in that country and who were diagnosed as having hemorrhagic dengue. One hundred and four of these subjects (comprising Group 1) were admitted to one of three major Havana hospitals and recovered. The other 26 (comprising Grupo 2) died. The information cited was obtained from the two groups' clinical histories, serologic testing of the Grupo 1 subjects, and autopsy reports on the Group 2 subjects. Age did no appear to be a risk factor among these adult subjects; but race and sex appeared to play a role in the disease, a disproportionate share of both groups being white and female. Classical dengue symptoms (fever, headache, asthemnia, myalgia, arthralgia, retroorbital pain, and occasionally rash) predominated in both groups. Digestive symptoms (nausea and vomiting, anorexia, abdominal pain, diarrhea, and hepatomegaly) were also common. Hemorrhagic symptoms were confirmed in 90. and 65. of the Group 1 and Group 2 subjects, respectively, and shock occurred in all the fatal cases. The study subjects typically developed classical dengue symptoms at the outset, followed by digestive and hemorrhagic symptoms. The Group 1 subjects recovered after an average of seven days of illness

Cuadro clínico de la fiebre hemorrágica del dengue/síndrome del choque del dengue en el adulto

Previous descriptions of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in adults have been limited. This article assesses the disease cases of 130 Cuban adults who became ill during the 1981 dengue epidemic in that country and who were diagnosed as having hemorrhagic dengue. One hundred and four of these subjects (comprising Group 1) were admitted to one of three major Havana hospitals and recovered. The other 26 (comprising Grupo 2) died. The information cited was obtained from the two groups' clinical histories, serologic testing of the Grupo 1 subjects, and autopsy reports on the Group 2 subjects. Age did no appear to be a risk factor among these adult subjects; but race and sex appeared to play a role in the disease, a disproportionate share of both groups being white and female. Classical dengue symptoms (fever, headache, asthemnia, myalgia, arthralgia, retroorbital pain, and occasionally rash) predominated in both groups. Digestive symptoms (nausea and vomiting, anorexia, abdominal pain, diarrhea, and hepatomegaly) were also common. Hemorrhagic symptoms were confirmed in 90

of the Group 1 and Group 2 subjects, respectively, and shock occurred in all the fatal cases. The study subjects typically developed classical dengue symptoms at the outset, followed by digestive and hemorrhagic symptoms. The Group 1 subjects recovered after an average of seven days of illness

and 65

Description of the clinical picture of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in adults

and 65

of the Group 1 and Group 2 subjects, respectively, and shock occurred in all the fatal cases. The study subjects typically developed classical dengue symptoms at the outset, followed by digestive and hemorrhagic symptoms. The Group 1 subjects recovered after an average of seven days of illness