Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial.

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.

The role of natural killer cells and antibody-dependent cell-mediated cytotoxicity during murine cytomegalovirus infection.

Definition of the functions by which the cellular immune system contributes to control of cytomegalovirus (CMV) infection should permit determination of the specific defects which result in the increased susceptibility to infection of immunosuppressed individuals. Using a murine model, we studied the cytotoxic lymphocyte response to murine CMV infection. This response was found to be biphasic. The initial phase extended from the 3rd to the 6th d after infection, was not genetically restricted, and correlated to a rise in numbers of natural killer (NK) and antibody-dependent killer (K) cells in spleens. The NK- and K-cell responses were preceded, by 24 h, by a rise in serum interferon levels, and occurred before the time when antibody could be measured in serum by neutralization. NK and K cells appear to develop the capacity for specific recognition of CMV-infected cells and the potential to contribute to control of the acute phase of CMV infection.

Sera from patients with the acquired immunodeficiency syndrome inhibit production of interleukin-2 by normal lymphocytes.

We studied the effects of sera from patients with the acquired immunodeficiency syndrome (AIDS) on interleukin-2 (IL-2) production to help elucidate the mechanism of immunodeficiency. Compared with sera from healthy controls, sera from AIDS patients suppressed phytohemagglutinin (PHA)-induced IL-2 production by normal blood mononuclear cells. Sera from homosexual contacts of AIDS patients and from adults with acute cytomegalovirus infection generally lacked this suppressive activity. The effect of the AIDS sera could not be attributed to absence of a stimulatory or nutritive factor, to inactivation of IL-2, to inhibition of the IL-2 assay, nor to increased turnover of IL-2. The suppressive effect of the sera was not mediated by radiosensitive or T8 antigen-bearing suppressor cells or by increased prostaglandin production or decreased interleukin-1 production. The sera acted directly on the groups of cells that produce IL-2, T cells and large granular lymphocytes; suppression occurred at an early, probably pretranslational, stage. When cells were incubated with AIDS sera and then washed, the suppressive effect persisted. The sera did not cause direct or complement-mediated cytotoxic effects on normal mononuclear cells nor did they suppress PHA-induced interferon production, nor proliferation of T lymphoblasts or lymphocyte lines. The suppressive effect was not mediated by interferon, cortisol, immunoglobulin G or M, or immune complexes. The activity was stable at pH 3, pH 10, and 60 degrees C; inactivated at 100 degrees C; and not ether extractable. Because IL-2 plays a central role in the development of many immune responses, the serum factor(s) that inhibits IL-2 production could contribute significantly to the immunodeficiency of AIDS.

Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome.

The recently described acquired immune deficiency syndrome (AIDS) is characterized by the occurrence of severe opportunistic infections and an aggressive form of Kaposi's sarcoma. A variety of profound defects in cell-mediated immunity have been reported in association with the AIDS, including deficiencies in natural killer (NK) cell activity and cytomegalovirus (CMV)-specific cytotoxicity. In the present study, the in vitro effects of interleukin-2 (IL-2) and interferon beta (IFN Beta) on these abnormalities were examined to assess the potential use of these lymphokines in the immunotherapeutic treatment of this syndrome. The peripheral blood lymphocytes (PBL) from six male homosexuals with AIDS and an active CMV infection exhibited markedly depressed NK cell and CMV-specific cytotoxic lymphocyte responses compared with uninfected, heterosexual control subjects. Incubation of PBL with IFN Beta enhanced the NK cell activity and the CMV-specific cytotoxicity of only one of six and neither of two AIDS patients, respectively, while enhancing the NK cell activity of all six control subjects. In contrast, IL-2 dramatically enhanced both the NK cell and the CMV-specific cytotoxic lymphocyte activities of all of the patients. These results indicate that IL-2 can substantially potentiate the depressed cytotoxic effector functions of PBL from AIDS patients, while IFN Beta has little effect.

Reactivity of an HIV gag gene polypeptide expressed in E. coli with sera from AIDS patients and monoclonal antibodies to gag.

A segment of the gag gene of the human immunodeficiency virus (HIV) (HTLV-IIIB strain), the virus which causes acquired immunodeficiency syndrome (AIDS), has been cloned into the bacterial expression vector, pCQV2, and mapped to the right-hand portion of the gag gene containing the carboxyl-terminal portion of p24 and the amino-terminal portion of p15. Nucleic-acid sequencing of the insert-vector junctions further defined the 5'-terminal nucleotide of HIV sequence as nucleotide 997 and the 3'-terminal nucleotide as 1696. When used in an enzyme-linked immunosorbent assay (ELISA) with sera from HIV-infected patients, the cloned antigen reacted with a subset of sera which were positive on a standard ELISA using whole virus as antigen. Western-blot screening of these sera with whole virus indicated that all p24-positive sera were positive with the clone, suggesting that the carboxyl-terminal portion of p24 contains a highly antigenic epitope(s). A serum which was p24-negative p15-positive by Western blot analysis was also highly reactive, indicating that a p15 epitope is present in the cloned antigen. Epitope mapping with a series of monoclonal antibodies to gag resulted in positive ELISA with 2 of 3 anti-p24, 0 of 1 anti-p15, and 0 of 1 anti-p17 Western-blot-positive monoclonal antibodies, suggesting that one of the anti-p24 monoclonal antibodies reacts with epitopes amino-terminal to those coded from nucleotide 997, two anti-p24 monoclonals react with epitopes carboxyl-terminal to those coded from nucleotide 997, and the anti-p15 monoclonal reacts with epitopes carboxyl-terminal to those coded from nucleotide 1696.

Influenza vaccine and pneumonia mortality in a nursing home population.

The effectiveness of immunization against influenza in elderly persons is uncertain. A retrospective cohort study in a New York City nursing home examined the occurrence of pneumonia and its related mortality over three consecutive influenza seasons (Nov 1 through April 30, 1979 to 1980, 1980 to 1981, and 1981 to 1982). Nearly one half of approximately 450 residents (mean age, 84 years) accepted immunization each year. The vaccinated and unvaccinated groups were similar. The attack rate of pneumonia did not differ significantly between the vaccinated and unvaccinated groups in any of the three influenza seasons. When influenza was occurring in the community (1979 to 1980 and 1980 to 1981), however, the risk of death from pneumonia in the unvaccinated group was three-fold higher than in the vaccinated group (60% vs 18% and 73% vs 25%, respectively). In a year when influenza was specifically sought and not found in the facility (1981 to 1982), however, vaccination did not affect pneumonia-related mortality. This study also suggests that estimates of mortality due to pneumonia should include deaths that occur up to 60 days after onset of pneumonia; shorter follow-up may overestimate the protective effect of vaccination.

Epidemiology of acute respiratory illness during an influenza outbreak in a nursing home. A prospective study.

We observed an influenza epidemic caused by influenza A/Arizona/82 (H3N2) in a nursing home during 1982 to 1983. A survey indicated that 59% of the residents were immunized before the outbreak. The outbreak was observed to begin in November, peak in February, and disappear in April. A significant level of herd immunity may have accounted for the slow progression through the nursing home. In addition, serologic evidence of concurrent infection with respiratory syncytial virus, parainfluenza virus, and Mycoplasma pneumoniae was present in many residents. Epidemics of influenza in a closed, partially immunized population in a nursing home may proceed at a slower rate than in an open, largely unimmunized community. By monitoring for infection with other respiratory agents, the complex nature of the outbreak in this nursing home became evident.

Association of influenza immunization with reduction in mortality in an elderly population. A prospective study.

We prospectively studied the efficacy of influenza vaccine during an influenza A/Arizona/80 (H3N2) outbreak at the Jewish Home and Hospital for the Aged in New York in the winter season of 1982 to 1983. All patients had been offered influenza vaccine before the outbreak; 181 chose to be vaccinated and 124 refused vaccination but agreed to participate in the study. Among those with serologic evidence of influenza infection, respiratory illness was significantly more common in the unvaccinated group (six of 14 vs one of 22). The overall mortality was 13 (7.2%) of 181 in the vaccinated group and 22 (17.7%) of 124 in the control group. The vaccinated and the control groups were examined for comparability. A logistic regression analysis, which controlled for differences in sex and level of nursing care, indicated that the difference in mortality was still significant, with a summary odds ratio of 2.7. The relative risk of death in the unvaccinated group was comparable at 2.18. Influenza vaccine reduced the mortality by 59% in the vaccinated group compared with the control group.

Human class I MHC-restricted cytotoxic T-lymphocytes specific for human immunodeficiency virus envelope antigens.

Vaccines incorporating HIV envelope antigens are being developed for the prevention of AIDS. To determine whether HIV envelope antigens are recognized by human cytotoxic T-lymphocytes (CTL), we assessed class I MHC-restricted, HIV envelope antigen-specific cytotoxic activity of peripheral blood mononuclear cells (PBMC) from HIV-infected individuals, following in vitro stimulation. The target cells were human skin fibroblasts of known tissue type, infected with recombinant vaccinia viruses, either containing or lacking the whole HIV envelope gene. Ten out of 17 (59%) asymptomatic HIV-seropositive individuals demonstrated HIV envelope antigen-specific cytotoxicity at levels that were above those seen in HIV-seronegative controls. MHC restriction of cytotoxicity was evident in that 13 out of 19 (68%) of the targets matched for the tissue type of the donor at one or more class I MHC loci were lysed, but only two out of 18 (11%) mismatched targets (P = 0.0004). Both partial purification of effector cells and evidence of MHC restriction indicated that T-lymphocytes were responsible for the observed cytotoxicity. HIV envelope antigen-specific CTL can be detected following in vitro stimulation of the PBMC in many asymptomatic HIV-seropositive individuals. HIV envelope antigens are recognized by human CTL and are, therefore, potentially relevant immunogens for induction of HIV-specific CTL responses.

Lack of evidence for HIV-2 infection among at-risk individuals in Brazil.

Recent reports have indicated the possibility that HIV-2 has been introduced into groups at risk for AIDS in Brazil. We studied sera collected in 1987 and 1988 from 1,821 at-risk individuals from diverse regions in Brazil. Of the 1,821 sera, 367 (20%) were confirmed as being positive for HIV-1 antibodies by enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), and Western blot. An additional 33 (2%) sera displayed some reactivity to HIV-2-infected cells by IF. All 33 sera were subsequently tested in HIV-1 and HIV-2 Western blots as well as an ELISA using HIV-1- or HIV-2-specific peptides. All sera were confirmed as positive for HIV-1 and negative for HIV-2 antibodies in both assays. We conclude that caution should be used in the interpretation of serologic cross-reactivity between HIV-1 and HIV-2 and that there is no evidence that HIV-2 has entered groups at risk for HIV infection in Brazil.

Human immunodeficiency virus neutralizing antibodies in sera from North Americans and Africans.

Neutralizing antibodies (NAs) against four isolates of human immunodeficiency virus type 1 (HIV-1) were assayed in HIV-1 antibody positive sera from the United States, Haiti, Zimbabwe, and Zaire. Overall, there were NAs detected in 95, 81, 60, and 73% of sera with reciprocal geometric mean titers (GMTs) of 626, 23, 10, and 20, respectively, against HIV-1MN, HIV-1IIIB, HIV-1RF, and HIV-1Z3. Sera from North America had significantly higher NA titers against HIV-1MN. In each country, the highest antibody titers observed were against the MN strain. Otherwise, sera from the U.S. neutralized most strongly HIV-1IIIB, sera from Zaire neutralized most strongly HIV-1Z3, and sera from Zimbabwe had equal titers against all three viruses. The differences between countries were reflected in analyses of NA titers of subgroups classified on the basis of clinical status, indicating that the differences were not likely to be related to differences in clinical status of the patients being tested. Some of this antigenic variation is reflective of known genetic diversity, while some is not. The results suggest that undefined preserved and variable regions containing neutralization epitope(s) exist. These data do not indicate a need to define antigenic subtypes of HIV-1 at present. The existence of conserved neutralization epitope(s) may indicate the potential for broad immunogenicity of appropriately selected vaccine antigens.

Importance of cytotoxic lymphocytes during cytomegalovirus infection in renal transplant recipients.

Thirty renal transplant recipients were studied prospectively to evaluate the relationship of cytomegalovirus-specific cytotoxic lymphocyte responses to clinical outcome during cytomegalovirus infection. Cytomegalovirus infection developed in 20 patients; of these 20, 14 had cytomegalovirus-specific cytotoxic lymphocyte responses whereas six did not. Clinical findings (fever, leukopenia, thrombocytopenia, or elevations in serum transaminase levels) were significantly more frequent among patients without responses than among patients with responses (p less than 0.001), and prolonged viremia and complications of infection including superinfection, interstitial pneumonitis, pancreatitis, and death occurred exclusively among patients without responses. Acute allograft dysfunction during infection was experienced by four patients without responses but by only one patient with response (p = 0.02), indicating that the virus-specific cytotoxic response did not result in a renal immunopathologic condition, and may have protected against virus-induced injury to the graft. In seven of nine patients with responses who shed virus, cytotoxic responses occurred within one week of detection of activation of virus shedding. Absence of cytotoxic responses correlated with prior high-dose, intravenous methylprednisolone treatment, and apparently resulted from inhibition of cytotoxic T cell precursors. Immunosuppressive treatment to inhibit graft rejection should be minimized, and methods should be developed that do not inhibit cytomegalovirus-specific cytotoxic T cell responses.

Five-year follow-up study of recipients of live varicella vaccine using enhanced neutralization and fluorescent antibody membrane antigen assays.

Twenty-six healthy children susceptible to varicella were inoculated with the OKA strain of live attenuated varicella vaccine. All of the recipients showed good antibody responses without adverse clinical reactions. The seropositivity rate 5 years after vaccination was 100% by the enhanced neutralization test and 96% by the fluorescent antibody membrane antigen (FAMA) test. None of the recipients contracted varicella in spite of documented contact exposure. None of the children developed herpes zoster during the 5-year observation period. The results suggest that attenuated varicella vaccine has long-term protective efficacy.

Potential for single high-dose influenza immunization in unprimed children.

High concentrations of split-product vaccine (SPV) are more immunogenic than lower concentrations. These studies were verified with another influenza strain, B/Singapore/22/79. Two ether-treated SPVs were compared in 80 children and young adults. The vaccine strains were influenza A/Bangkok/79, A/Brazil/78, and B/Singapore/79; 44 patients received a high-dose SPV containing 7, 7 and 60 micrograms each of the respective hemagglutinins (HA) and 36 received a standard dose SPV containing 7, 7, and 7 micrograms of HA, respectively. Among persons initially seronegative by hemagglutination inhibition (HAI) tests, the geometric mean titer (GMT) in 15 recipients of one high dose was 97 vs GMT of 37 in 18 recipients of one standard dose (P less than .05). Furthermore, 87% of high-dose recipients had HAI titer greater than or equal to 40 vs 44% of standard dose recipients. In initially seropositive persons, GMT in 29 recipients of one high dose was 170 vs GMT of 84 in 18 recipients of one standard dose (P less than .05). Immune response to the other two virus strains was comparable for the two vaccines. The reaction index for the high dose vaccine was 0.70 vs 0.45 for the standard dose (P = NS). An A/Bangkok epidemic struck the New York metropolitan area. The attack rate in unvaccinated matched sibling control subjects was 35% (15/43). There were no vaccine failures. In conclusions, in the small number of patients studied, a 60-micrograms HA dose of B/Singapore/79 was significantly more immunogenic than a standard 7-micrograms HA dose without an increase in reactogenicity.

Preparation and characterization of human HIV type 1 neutralizing reference sera.

Reference neutralizing antibody (NA) reagents are needed for laboratories to be able to compare results of neutralization assays that will be used to monitor HIV-1 vaccine recipients. In an effort to establish such reference reagents two asymptomatic, seropositive patients were identified with medium to high amounts of cross-reactive NA activity against a number of HIV-1 strains. Sera obtained from each individual at three or four sequential phlebotomies were pooled, and the two pools were each distributed in > 3000 aliquots into glass ampoules and lyophilized, and the ampoules were flame sealed. An HIV-1 antibody-negative reference serum was prepared in a similar fashion after pooling serum from four individuals. Ampoules were tested for uniformity of fill, sterility, moisture content, residual oxygen, stability, infectivity, and presence of antibody. An international collaborative study was conducted to determine the potency of the samples in six laboratories, each using their own neutralization assays and reagents. The results indicated reasonable consistency between laboratories and that both sera have sufficient titers against a variety of strains for use as reference reagents. These reference sera have been included in the World Health Organization (WHO) AIDS Reagent Project and are available through the three AIDS reagent repositories.

International collaborative study to compare assays for antibodies that neutralize human immunodeficiency virus.

A variety of techniques are currently in use to measure antibodies that neutralize human immunodeficiency virus (HIV), and standardization of these assays is needed. Eleven laboratories participated in this comparison study of 14 methods for detection of HIV neutralizing antibodies (NA). A panel of 10 coded sera and a positive and a negative control serum were tested in each assay. The 10 coded samples included aliquots of the same sera that were distributed as positive and negative control sera, an aliquot of the WHO reference human anti-HIV-1 serum, and seven other sera from people with HIV-1 infection. Each laboratory reported features of its test methods and results. The results demonstrated excellent within laboratory and between laboratory consistency. The most important variable appeared to be the virus strain used. Cell line, conditions of neutralization or culture, method of endpoint determination, or use of VSV pseudotypes did not appear to be important variables. The results indicate that standardization of HIV-1 NA assays should be readily achievable.

Expression and characterization of HIV type 1 envelope protein associated with a broadly reactive neutralizing antibody response.

We have studied envelope protein from a donor with nonprogressive HIV-1 infection whose serum contains broadly cross-reactive, primary virus NA. DNA was extracted from lymphocytes, which had been collected approximately 6 and 12 months prior to the time of collection of the cross-reactive serum, and env genes were synthesized, cloned, expressed on pseudoviruses, and phenotyped in NA assays. Two clones from each time point had identical V3 region nucleotide sequences, utilized CCR5 but not CXCR4 for cell entry, and had similar reactivities with reference sera. Analysis of the full nucleotide sequence of one clone (R2) demonstrated it to be subtype B and have normal predicted glycosylation. R2 pseudovirus was compared with others expressing env genes of various clades for neutralization by sera from U.S. donors (presumed or known subtype B infections), and from individuals infected with subtypes A, C, D, E, and F viruses. Neutralization by the U.S. sera of R2 and other clade B pseudoviruses was low to moderate, although R2 was uniquely neutralized by all. R2 was neutralized by 3/3, 3/3, 2/5, 5/8, and 3/4 clade A, C, D, E, and F sera, respectively. R2 and a clade E pseudovirus were neutralized by largely complementary groups of sera, potentially defining two antigenic subgroups of HIV-1. The results suggest that the epitope(s) that induced the cross-clade reactive NA in donor 2 may be expressed on the R2 envelope.

Evolution of neutralizing antibody response against HIV type 1 virions and pseudovirions in multicenter AIDS cohort study participants.

Changes in neutralizing antibody (NA) titers in stored sera collected over 5 years from 10 participants in the Multicenter AIDS Cohort Study (MACS) were evaluated. The participants were HIV-1 infected on enrollment in the MACS, and remained AIDS free during the 5-year study interval. Seven viruses derived from molecular clones were used in NA assays; five of the viruses were T tropic (NL4-3, ALA1, NY5, SF2, and Z2Z6) and two were M tropic [AD8 and NL(SF162)]. In addition, pseudoviruses (PVs) were constructed that expressed envelope genes from NL4-3, ALA1, AD8, and SF162 and from primary viruses from two MACS participants (PV-9 and PV-10). There was significant correlation between NA titers obtained in four of five virus/PV comparisons, while the SF162 PV was more sensitive to NA than the corresponding virus. Comparable changes in NA titers were detected using viruses and PVs. Fourfold or greater increases in NA titers were noted in each of the participants, involving recognition of one to five of the nine strains tested. In some patients these NA titer changes appeared as discrete episodes of immune responses, while in others there may have been either multiple episodes or continuous evolution of the NA responses. The data indicate that changes in NA specificity occur during HIV-1 infection, which may result from the occurrence of neutralization escape mutation. The use of PVs for the study of phenotypic characteristics of envelope glycoproteins should facilitate the study of neutralization escape mutation in HIV-1 infection.

High prevalence of antibodies to the gp120 V3 region principal neutralizing determinant of HIV-1MN in sera from Africa and the Americas.

Neutralizing antibodies (NA) against HIV-1MN and HIV-1IIIB, and antibodies binding to synthetic peptides (BA) derived from the gp120 envelope V3 region principal neutralizing determinants (PND) of the HIV-1MN, HIV-1IIIB, and HIV-1Z3 virus strains were assayed in HIV-1 antibody-positive sera from the United States, Haiti, Brazil, Zaire, and Zimbabwe. The ability of soluble PND peptide to block neutralization of the corresponding virus by representative sera was also tested. In each country, NA and BA titers were highest against the HIV-1MN strain, and compared with other countries, NA and BA titers against HIV-1MN were higher in sera from the United States and Haiti. When NA titers were compared with BA titers against either HIV-1MN or HIV-1IIIB, no correlation was found for the HIV-1IIIB strain, but there was a significant correlation for HIV-1MN. Addition of the HIV-1MN strain peptide to a neutralization assay for HIV-1MN resulted in a four- to tenfold reduction in NA titers in sera from the United States, Zaire, and Brazil. The results suggest that HIV-1MN and closely related variants are prevalent in many parts of the world, and that antibodies directed against the PND account for most of the neutralizing activity in sera of infected individuals.

PIP: Virologists assessed the extent of neutralizing antibody cross-reactivity to multiple virus strains in sera from 112 HIV-1 infected individuals from the US, Brazil, Haiti, Zaire, and Zimbabwe. They also looked at the association between virus neutralization and the level of antibody binding to synthetic peptides representing the HIV-1 gp120 V3 region principal neutralizing determinant (PND) sequences. The 3 strains observed included HIV-1 MN, HIV-1 Z3, and HIV-1 IIIB. Neutralizing antibodies (NA) and antibodies binding to synthetic peptides (BA) titers ranked highest against the PND sequence HIV-1 MN in all countries (p.01). These titers were higher in sera from the US and Haiti than sera from Brazil and Africa (p.05). A significant correlation existed between the NA and BA titers for HIV-1 MN (p.01), but not for HIV-1 IIIB. When the virologists added HIV-1 MN strain peptide to a neutralization assay for HIV-1 MN, NA titers in sera from the US, Zaire, and Brazil fell 4-10 fold. These findings intimated that HIV-1 MN and closely related variants are commonplace in several locations around the world, and that antibodies directed against HIV--1 gp120 V3 region PND sequences make up most of the neutralizing activity in sera of infected individuals. In conclusion, virologists need to conduct more studies that examine the true extent of strain variation worldwide. These studies could lay the groundwork for the development of an effective HIV-1 vaccine.

Immunization of elderly people with high doses of influenza vaccine.

Healthy ambulatory elderly were immunized with increasing doses of the 1984-1985 influenza vaccine formulation. Two types of vaccines, split-product vaccine (SPV) and whole virus vaccine (WVV), were used. Three different doses, 0.5 mL (the standard volume, 1X), or 1.0 mL (2X), and 1.5 mL (3X) of each of the two vaccines were compared. The size of each of the six groups was between 23 and 26 subjects. The mean ages in each of the groups ranged from 71 to 74 years. No difference in local or systemic reaction was noted among the six groups. A dose-response effect was observed for the SPV recipients to the influenza A/Chile/83 (H1N1) strain. The geometric mean hemagglutination inhibition (HI)titer (GMT) was 1:76 after the 3X dose vs 1:38 after the 1X dose (P less than 0.025). To the influenza A/Philippines/82 (H3N2) strain the GMT was 1:70 after the 3X dose vs 1:43 after the 1X dose. A similar trend was noted for the influenza B/USSR/83 strain. A (HI) titer of greater than or equal to 1:40 for all the strains was seen in greater than 70% of the split product vaccine recipients only after the 3X dose. For the WVV recipients, increasing doses did not result in increasing GMT for any of the three vaccine strains. In addition, HI titers greater than or equal to 1:40 were not uniformly seen in greater than 70% of the vaccine recipients at any of the three whole virus vaccine doses.(ABSTRACT TRUNCATED AT 250 WORDS)