A Phase I Evaluation of the Safety and Immunogenicity of Vaccination with Recombinant gp160 in Patients with Early Human Immunodeficiency Virus Infection
List of authors.Abstract
Background.
Despite multiple antiviral humoral and cellular immune responses, infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by postinfection vaccination with HIV-specific antigens.
Methods.
We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0, 30, and 120 or on days 0, 30, 60, 120, 150, and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination, including general measures of immune function, were monitored.
Results.
In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with >600 cells per milliliter responded, as compared with 6 of 14 [43 percent] with ≤600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded, as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions, including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up, the mean CD4 count had not decreased in the 19 subjects who responded, but it had decreased by 7.3 percent in the 11 who did not respond.
Conclusions.
This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful, further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections. (N Engl J Med 1991; 324: 1677–84.)
Methods
A more detailed description of our methods is available from the National Auxiliary Publications Service.*
Selection of Subjects
Thirty volunteer subjects with HIV infection were recruited from among Department of Defense health care beneficiaries. The nature of the trial was explained in detail to each subject, and written informed consent was obtained. Only seropositive patients in an early stage of HIV infection, defined as Walter Reed stage 1 or 2 (a CD4 cell count of not less than 400 per milliliter for more than three months, with or without lymphadenopathy),13 were eligible for enrollment. The subjects also had to be between 18 and 50 years old, have a normal complete blood count, have no evidence of endorgan disease, have not abused alcohol or drugs over the preceding 12 months, and have not received antiretroviral or immunomodulatory drugs. All the subjects underwent a two-month base-line evaluation before randomization. None received any antiretroviral or immunomodulatory drug during the trial.
Vaccine Product and Immunization Schedule
The test vaccine was a noninfectious subunit glycoprotein derived from human T-cell lymphotropic virus Type III, gp160 (VaxSyn HIV-1, MicroGeneSys, Meriden, Conn.), a baculovirus-expressed recombinant protein produced in the cells of lepidopteran insects, biochemically purified, and adsorbed to aluminum phosphate for final formulation.29 Three doses of gp160 were used: 40, 160, and 640 μg. Both the 40-μg and 160-μg doses were injected in a volume of 1 ml; the 640-μg dose was given as 320 μg per milliliter in a volume of 2 ml.
Table 1.
Table 1. Immunization Schedule. The 30 subjects were assigned to six vaccination groups of 5 subjects each. Two immunization schedules were investigated: schedule A, with vaccination on days 0, 30, and 120, and schedule B, with vaccination on days 0, 30, 60, 120, 150, and 180. Three of the six groups received different doses of vaccine according to schedule A, and the other three groups received different doses according to schedule B (Table 1). All vaccinations were administered by intramuscular injection into the deltoid muscle. The duration of the trial was 10 months — i.e., a 2-month base-line evaluation and an 8-month follow-up evaluation after the initial vaccination.
Assessment of Safety
Each subject was interviewed and examined on days 0, 1, 2, 3, 15, and 30 after each injection. They were asked whether they had had fever, chills, nausea, vomiting, arthralgia, myalgia, malaise, urticaria, wheezing, dizziness, or headache and were examined for local reactions at the site of injection, including erythema, swelling, itching, pain and tenderness, skin discoloration, skin breakdown, any change in regional lymphadenopathy, any change in the function of the extremity into which the vaccine had been injected, and the formation of any subcutaneous nodules at the site of injection. The complete blood count, serum biochemical determinations, coagulation-profile assessment, and urinalysis were performed monthly.
In vitro cellular immune function was assessed by determining the T-cell phenotype (total-lymphocyte, CD4 cell, and CD8 cell phenotypes)30,31 and the T-cell proliferative response to mitogens (pokeweed and concanavalin A) and control antigens (Candida albicans and tetanus).31 In vivo cellular immune function was assessed by skin testing for delayed hypersensitivity to control antigens (mumps, tetanus toxoid, C. albicans, and trichophyton).
Quantitative viral culture of peripheral-blood mononuclear cells and plasma,22 DNA polymerase-chain-reaction testing,32 and measurement of serum p24 antigen levels were performed to monitor the HIV viral load in vivo.
Assessment of Immunogenicity
Table 2.
Table 2. Humoral Response (Antibody to HIV Envelope Epitope) and Cellular Response (T-Cell Proliferation) to Vaccination.* Antibodies directed against whole HIV proteins were measured with both recombinant viral gene products gp160, p66, and p24 (MicroGeneSys) and whole viral lysate of prototype HIV strain MN by dot blotting and Western blotting techniques.33 Antibody responses to specific envelope epitopes were also measured (Table 2).
Neutralization activity was measured against three prototype HIV isolates (IIIB, RF, and MN) in a syncytium inhibition assay.47 HIV-specific cellular responses were measured by standard lymphocyte-proliferation-assay techniques with use of gp160, p24, and baculoviral-expression-system control protein.31 A detailed description of the methods for assessing safety and immunogenicity is available elsewhere.*
Definition of Response
The subjects were classified as responding to vaccination if they had a reproducible selective increase in both a cellular and a humoral immune response against HIV envelope-specific epitopes that was temporally associated with the series of vaccinations. Vaccine-induced humoral immunity was indicated by seroconversion to HIV envelope-specific epitopes, a secondary booster immune response to envelope-specific epitopes, or both. Vaccine-induced cellular immunity was indicated by the development of a new, reproducible, temporally associated proliferative response to gp160.
Subjects with neither a humoral nor a cellular proliferative response, or only a humoral or only a cellular proliferative response, to gp160 epitopes or HIV envelope epitopes were classified as not having responded to the vaccination.
Statistical Analysis
Proportions were compared by Fisher's exact test (two-sided). Changes in cellular immune responses were summarized as the magnitude of changes (fold change) in the lymphocyte-stimulation index. The fold change for each subject was calculated by dividing the mean of the values for the index that were measured after the last vaccination by the mean of the values for the index at base line. Differences between subgroups in cellular immune responses were assessed by comparing the distributions of fold changes by the Wilcoxon rank-sum test. Changes in the number of CD4 T lymphocytes were compared between subgroups of subjects and with the change expected on the basis of experience with the natural history of HIV infection. Comparisons between subgroups were based on the mean of the percent changes in CD4 cell counts at the end of the follow-up period, as compared with the means at base line. At each time point, the number of CD4 T lymphocytes was calculated as the mean of seven values (the median was determined according to the time point).
Results
Demographic and Base-Line Clinical Characteristics
Twenty-six of the 30 subjects were men, and 4 were women. Fourteen were non-Hispanic whites, 13 were black, and 3 were Hispanic. Their mean age was 29 years (range, 18 to 49). At enrollment 8 subjects had HIV infection in Walter Reed stage 1, and 22 had infection in stage 2. The base-line mean CD4 cell count was 668 per milliliter (range, 388 to 1639). The mean time between initial diagnosis and study entry was 24 months (range, 3 to 49).
Vaccine-Induced Humoral Responses
All 30 subjects completed the 240-day trial. Nineteen (63 percent) had a vaccine-induced augmentation of both HIV gp160-specific humoral and cellular immune responses and thus were classified as "vaccine responders." Of the 11 subjects classified as "nonresponders," 4 had only a humoral or a cellular immune response and 7 had no detectable response; all 7 without a response had received only three doses of vaccine (schedule A). No subject had changes in antibody binding to HIV polymerase (p66) or structural (p24) gene products or to the non-HIV control antigen tetanus. No antibody to the baculoviral lepidopteran-cell control protein developed in any subject.
Increases in the level of envelope antibody (gp160) were detected in 13 subjects on Western blotting with the whole-virus lysate HIV-MN. These changes were related to the immunization schedule. Three of 15 subjects (20 percent) assigned to schedule A and 10 of 15 (67 percent) assigned to schedule B had an increase in the level of antibody to envelope proteins (P = 0.025 by Fisher's exact test, two-tailed). All 13 subjects also seroconverted to specific envelope epitopes. Conversely, of the 10 subjects who did not seroconvert to any envelope-specific epitope, none had an increase in envelope-antibody levels on Western blotting. The remaining seven subjects who seroconverted to specific envelope epitopes had no change in whole-virus envelope antibody on Western blotting. No changes in antibody directed against non-HIV envelope proteins were observed in any subject.
Figure 1.
Figure 1. Prevalence of Vaccine-Induced Antibody Directed against Specific HIV Envelope Epitopes, before Immunization (Open Bars) and after Immunization (Solid Bars, Study Day 195 to 240), According to Immunization Schedule. Three injections were given during schedule A, and six during schedule B.
Fourteen of 15 subjects (93 percent) assigned to schedule B (six doses) had an increase in total gp160 antibody, as opposed to only 7 of 15 (47 percent) assigned to schedule A (three doses) (P = 0.01 by Fisher's exact test, two-tailed) (Table 2). The range of the prevalence of 11 of the 12 gp160-specific epitopes selected for study (Table 2), from before to after vaccination, was as follows: epitope 49, 27 to 70 percent; epitope 88, 28 to 52 percent; epitope 106, 50 to 87 percent; epitope 241, 0 to 14 percent; epitope 254, 0 to 13 percent; epitope 300, 47 to 77 percent; epitope 308, 42 to 69 percent; epitope 342, 0 to 27 percent; epitope 422, 3 to 10 percent; epitope 448C, 73 to 87 percent; and epitope 735, 17 to 33 percent (Fig. 1). Vaccine-induced seroconversion was noted to all the specific epitopes, except epitope 582 (Table 2). Antibodies (seroconversion) directed against epitopes 241, 254, and 342 were detected only after vaccination (Table 2).
Secondary immune responses to epitopes 88, 106, 300, 308, 448C, and 582 were elicited (Table 2). The prevalence of antibody directed against epitope 582 was 100 percent before vaccination, and only one subject (3 percent) had a secondary immune response.
The pattern of vaccine-induced HIV antibody to envelope epitopes was variable (Table 2). Primary antibody responses (seroconversion) to at least one epitope occurred in 20 subjects — 14 of 15 assigned to schedule B and 6 of 15 assigned to schedule A (P = 0.005 by Fisher's exact test, two-tailed). Furthermore, of all the epitopes studied, subjects assigned to schedule A seroconverted to only 15 of 110 (14 percent) of the potential epitopes to which they had no antibodies before vaccination, whereas subjects assigned to schedule B seroconverted to 60 of 129 potential epitopes (47 percent) (P<0.0001 by Fisher's exact test, two-tailed). Seroconversion to three or more envelope epitopes occurred in 9 subjects (60 percent) assigned to schedule B but in only 2 (13 percent) of those assigned to schedule A (P = 0.02 by Fisher's exact test, two-tailed).
Serum neutralization activity against three distinct strains (HIV-IIIB, HIV-MN, and HIV-RF) was determined on days 0, 90, and 195 in seven subjects. Four of five responders had increasing neutralizing activity to one or more isolates, as compared with neither of two nonresponders. Furthermore, the responders as a group, unlike the nonresponders, had an increase in the percentage of inhibition at a given dilution of serum required to inhibit syncytium formation against each prototype isolate tested.
Vaccine-Induced Cellular Responses
Figure 2.
Figure 2. Vaccine-Induced T-Cell Proliferation of gp160 in Four Responders, as Reflected by the Lymphocyte-Stimulation Index (LSI). Arrows denote the days on which immunizations were administered. The LSI responses to gp160 are represented by open circles, those to p24 by open squares, and those to the expression-system baculoviral control protein by solid triangles. Note the temporal relation between vaccination and the increase in gp160 proliferative response.
Figure 3.
Figure 3. Lymphocyte Proliferative Responses Associated with Vaccination. Open bars represent the mean (±SEM) change in base-line values for the lymphocyte-stimulation index (LSI), and solid bars the mean values of the four sequential LSI values measured after the last immunization in each subject. Values are shown for all subjects combined, subjects grouped according to responsiveness, and subjects grouped according to immunization schedule. The HIV protein sources gp160 and p24 were produced by a lepidopteran baculoviral expression system; BCP represents the expression-system baculoviral control protein.
In 21 of 30 subjects (70 percent), a new T-cell proliferative response to gp160 developed after vaccination (Table 2). Figure 2 shows the time course of proliferative responses to gp160, p24, and a baculovirus control protein in four typical vaccine responders. In all subjects, the gp160-induced proliferation increased, in that the mean lymphocyte-stimulation index rose from 3 at base line to 10 (a value calculated from the mean of four values determined after the last immunization). In contrast, no change was noted in the proliferative responses directed against HIV p24 protein or the control baculovirus protein. Vaccine-induced changes in the mean lymphocyte-stimulation index for all subjects, for subjects grouped according to degree of response, and for subjects grouped according to immunization schedule are shown in Figure 3. The change in proliferative response to gp160 in the vaccine responders was significantly different from that in the nonresponders (P<0.001 by Wilcoxon test, one-tailed). The proliferative responses induced by the six injections of gp160 according to schedule B were greater than those induced by the three injections according to schedule A (Fig. 3) (P<0.10 by Wilcoxon test, one-tailed).
Nineteen of the 21 subjects who had proliferative responses to gp160 also had a humoral response (the 19 responders). The maximal mean lymphocyte-stimulation index observed among all 19 responders in response to gp160 was 50.1. However, in each responder the index was variable (range of peak values, 3 to 171) (Table 2), as was the temporal relation between vaccination and the magnitude and duration of the cellular responses to gp160 (Fig. 2).
Predictors of Immune Responsiveness
Table 3.
Table 3. Immune Responsiveness to Vaccination, According to Immunization Schedule and Base-Line CD4 Count. Despite the limited size of the sample in this trial, several factors were demonstrated to be associated with vaccine-induced immunogenicity. Six of 15 (40 percent) of the subjects assigned to schedule A responded, as compared with 13 of 15 (87 percent) of those assigned to schedule B (P = 0.02 by Fisher's exact test, two-tailed) (Table 2). Of the 16 subjects with a mean base-line CD4 count greater than 600 per milliliter, 13 (81 percent) were responders, as opposed to 6 of 14 (43 percent) whose mean CD4 count at entry was 600 or fewer cells per milliliter (P = 0.07 by Fisher's exact test, two-tailed). Multiple immunizations improved immunogenicity, even among patients with base-line CD4 counts of 600 or fewer cells per milliliter; five of six subjects with such counts assigned to schedule B (six injections) were responders, as compared with only one of eight assigned to schedule A (three injections) (P = 0.03 by Fisher's exact test, two-tailed; Table 3).
Toxicity
No evidence of systemic toxicity was observed, but local reactions were noted in 87 percent of the subjects (13 in each vaccination group). These reactions included induration, tenderness, and transient subcutaneous nodule formation at the injection site; an increase in regional adenopathy was rarely noted. No subject refused a booster injection. No difference in the frequency of local reactions was observed in relation to primary immunization, booster injection, or vaccine dosage.
Figure 4.
Figure 4. Change from Base Line in the CD4 Cell Count in Responders and Nonresponders. Each base-line value represents the mean CD4 count at all pre-immunization evaluations performed during the two months before the initial vaccination (four to six values per subject). Each point represents a moving average of seven values (see Methods).
No evidence of an adverse effect on the immune system was demonstrated, as measured in vitro by mitogen-specific and antigen-specific proliferative responses, in vivo by responses to delayed-hypersensitivity skin testing, or by acceleration of quantitative CD4 cell depletion. At base line the mean CD4 cell count was 716 in the responders and 605 in the nonresponders; from study day 180 to day 240 the mean count was 714 and 561, respectively. During the course of the 240-day trial, the net change in the mean CD4 cell count amone the responders was a decrease of 0.2 percent, whereas among the nonresponders it was a decrease of 7.3 percent (Fig. 4). Vaccine-induced immunogenicity to HIV was not associated with evidence of an accelerated decline in the CD4 count of any subject throughout the entire course of the trial.
To assess the possibility of increased HIV replication and viral load in the subjects as a consequence of vaccination, in vivo viral activity was measured by quantitative cultures of the virus in plasma and peripheral-blood mononuclear cells, by the polymerase-chain-reaction testing of DNA from peripheral-blood mononuclear cells, and as serum levels of p24 antigen. Assay by quantitative culture and the polymerase chain reaction demonstrated no changes during this trial. Serum p24 antigen was undetectable in all subjects.
Discussion
The therapeutic use of vaccines was introduced by Pasteur in the 19th century for the treatment of acute rabies infection, but the value of this approach in the treatment of other infections has not been extensively explored. Although there are other examples of postinfection modification of viral-specific immunity (for example, after exposure to hepatitis A or B), there are no well-documented studies in humans that have demonstrated the feasibility of this approach in the setting of an established or chronic viral infection. Even in animals the only suggestion that such an approach is feasible is limited to a single investigation of herpes simplex in guinea pigs.48
The present study demonstrates the feasibility of virus–specific immune modification by active immunization after infection. Specifically, a gp160 vaccine derived from an HIV envelope gene augmented host-directed viral-specific humoral and cellular responses in 19 of 30 persons with early HIV infection. The definition of vaccination response that we chose —i.e., the requirement that a response be both humoral and cellular — was arbitrary but highly restrictive in the light of the scientific objective of this trial to assess the feasibility of postinfection immunization, and in the absence of support for this concept in studies of other chronic viral infections.
By qualitative and quantitative measurement of distinct antibody responses to specific HIV epitopes in natural infection as opposed to postinfection immunization, vaccine-induced humoral immunogenicity in already infected persons was documented in 70 percent of the subjects. Although gross analysis of whole viral proteins by the Western blotting technique was helpful, characterization of humoral response by mapping of distinct epitopes proved to be a more sensitive method of assessing immunogenicity. Seroconversion to specific envelope epitopes occurred in 20 subjects (19 vaccine responders and 1 nonresponder) (Table 2). In addition, seroconversion associated only with vaccination (conversion to epitopes 241, 254, and 342) occurred in 10 subjects. This variation in humoral responses to the gp160 vaccine, as characterized by epitope mapping, will permit prospective cause- and- effect analysis of specific antibody responses and presents unique opportunities to characterize potential immunoregulatory mechanisms not elicited during a natural infection.
Although the relevance of serum neutralizing activity in vivo is unknown at present, the observation of increased neutralizing activity against disparate strains of HIV (IIIB, RF, and MN) in four of five responders suggests that postinfection immunization induced changes in functional antibody. This vaccine-induced increase in serum neutralization capacity against distinct strains of HIV will potentially aid in the definition of group-specific neutralization epitopes.
A proliferative response to HIV envelope proteins rarely occurs in natural HIV infection (data not shown). After immunization with gp160, however, specific T-cell proliferative responses were documented in 21 (70 percent) of the subjects. The reason for this difference is unclear. One possibility is that the new proliferative response may be directed against an envelope epitope (or epitopes) unique to the vaccine (as a result of the methods of vaccine production or antigen processing in vivo). Alternatively, the protein used in the proliferation assay may not stimulate primary T-cell proliferative responses against homologous wild-type envelopes of natural virus. We have recently obtained additional evidence that vaccination may boost the host cellular immune response: in selected responders to vaccination, HIV-IIIB type—specific cytotoxic T-cell responses were induced after booster immunization (data not shown).
The factors responsible for immunoresponsiveness to vaccination in HIV-infected persons remain to be clarified. Even in early HIV infection, individual patients respond suboptimally to a variety of vaccines, as compared with matched controls.49 This hyporesponsiveness has been related to early B-cell dysregulation and T-cell dysfunction.31 , 50 In the present trial, immunoresponsiveness to vaccination was associated with the base-line CD4 cell count, a finding consistent with the hypothesis that the immunologic status of a host is an important determinant of responsiveness. However, the immunization schedule within specific T-cell—count intervals (Table 3) also influenced responsiveness: schedule B (six injections) was superior. Indeed, the decreased response observed in the subjects with lower CD4 cell counts could be improved by an increased number of vaccinations, which suggests that further modifications in the dosage, regimen, adjuvant treatments, or formulation may improve host immunoresponsiveness.
Although questions have been raised about the safety of active immunization of HIV-infected persons with HIV-specific vaccine products,51 there was no evidence of immune-specific toxicity. Quantitative cultures, DNA polymerase-chain-reaction assays, and serum antigen assays did not document any evidence of increased HIV load in vivo. Moreover, an excellent in vivo surrogate marker of HIV replication — the rate of decline in the CD4 cell count — was favorably influenced among the subjects, especially those classified as responders, in whom the decrease in the mean CD4 count was 0.2 percent, as compared with 7.3 percent in nonresponders. These data demonstrate that postinfection immune responsiveness was not associated with an increase in CD4 cell destruction, but perhaps rather with decreased replication of HIV in vivo. A more direct measurement of in vivo active expression of virus — RNA-transcript analysis — is under development.52
An open, unblinded, phase I trial is not designed to provide conclusive information about therapeutic efficacy. Thus, the ability to respond to gp160 with either a primary or a secondary immune response may have been restricted to a subgroup of patients who had less severe B-cell or T-cell dysfunction. The difference observed between the base-line mean CD4 counts of responders and those of nonresponders (716 and 605 cells per milliliter, respectively) and the overall poor response of subjects with CD4 counts of 600 cells or fewer per milliliter at entry support this possibility. However, because of the grim prognosis of patients with this infection, we believed it was important to explore potential clinical benefits. Thus, we retrospectively compared changes in the subjects' mean CD4 cell counts according to treatment group (vaccination schedules) with expected changes observed during untreated infections, using a data base on the natural history of HIV infection in a cohort of patients from the U.S. Army. Ten patients from this cohort were matched for age, ethnic group, and base-line CD4 cell count with each subject. The mean CD4 count decreased by 8.7 percent in this historical reference group, decreased by 7.2 percent in subjects assigned to schedule A, and increased by 0.6 percent in subjects assigned to schedule B. Although preliminary, these results are encouraging. Direct evidence of therapeutic benefit must await the completion of phase II studies of clinical efficacy.
In the light of these results, the scientific and therapeutic importance of HIV-specific immunization warrants further investigation. Postinfection vaccination should serve as a powerful tool to further the understanding of HIV immunoregulation and, if proved clinically relevant, would provide an alternative strategy for treatment. This approach may also prove useful in defining a protective immune response (or responses) relevant to the prophylactic use of vaccines.
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Citing Articles (180)
Letters
Figures/Media
- Table 1. Immunization Schedule.
Table 1. Immunization Schedule. - Table 2. Humoral Response (Antibody to HIV Envelope Epitope) and Cellular Response (T-Cell Proliferation) to Vaccination.*
Table 2. Humoral Response (Antibody to HIV Envelope Epitope) and Cellular Response (T-Cell Proliferation) to Vaccination.* - Figure 1. Prevalence of Vaccine-Induced Antibody Directed against Specific HIV Envelope Epitopes, before Immunization (Open Bars) and after Immunization (Solid Bars, Study Day 195 to 240), According to Immunization Schedule.
Figure 1. Prevalence of Vaccine-Induced Antibody Directed against Specific HIV Envelope Epitopes, before Immunization (Open Bars) and after Immunization (Solid Bars, Study Day 195 to 240), According to Immunization Schedule. Three injections were given during schedule A, and six during schedule B.
- Figure 2. Vaccine-Induced T-Cell Proliferation of gp160 in Four Responders, as Reflected by the Lymphocyte-Stimulation Index (LSI).
Figure 2. Vaccine-Induced T-Cell Proliferation of gp160 in Four Responders, as Reflected by the Lymphocyte-Stimulation Index (LSI). Arrows denote the days on which immunizations were administered. The LSI responses to gp160 are represented by open circles, those to p24 by open squares, and those to the expression-system baculoviral control protein by solid triangles. Note the temporal relation between vaccination and the increase in gp160 proliferative response.
- Figure 3. Lymphocyte Proliferative Responses Associated with Vaccination.
Figure 3. Lymphocyte Proliferative Responses Associated with Vaccination. Open bars represent the mean (±SEM) change in base-line values for the lymphocyte-stimulation index (LSI), and solid bars the mean values of the four sequential LSI values measured after the last immunization in each subject. Values are shown for all subjects combined, subjects grouped according to responsiveness, and subjects grouped according to immunization schedule. The HIV protein sources gp160 and p24 were produced by a lepidopteran baculoviral expression system; BCP represents the expression-system baculoviral control protein.
- Table 3. Immune Responsiveness to Vaccination, According to Immunization Schedule and Base-Line CD4 Count.
Table 3. Immune Responsiveness to Vaccination, According to Immunization Schedule and Base-Line CD4 Count. - Figure 4. Change from Base Line in the CD4 Cell Count in Responders and Nonresponders.
Figure 4. Change from Base Line in the CD4 Cell Count in Responders and Nonresponders. Each base-line value represents the mean CD4 count at all pre-immunization evaluations performed during the two months before the initial vaccination (four to six values per subject). Each point represents a moving average of seven values (see Methods).
