ASIAN PACIFIC JOURNAL OFALLERGR AND IMMUNOLOGY (1997) 15: 105-113

International Clinical Trials of HIV : II. Phase I Trial of an HIV-1 Synthetic Peptide Evaluating an Accelerated Schedule Iw in Yunnan, China

Detu Li, Bruce D Forrest, Zhirong Li, Ping Xue, Carl V Hanson, Song Duan, Hehe Cheng. Minglie Li. Chang Yi Wang and Wayne C Koff t i l ! The development of a safe and SUMMARY A Phase 1, double-blind, placebo controlled trial was conduc­ globally effective HIV vaccine will ted in Longchuan County, China, to evaluate the safety and immunogenicity require the parallel development of of a prototype HIV-1 synthetic peptide vaccine in a target population at risk candidate vaccines capable of for HIV , and to establish the infrastructure for future large-scale HIV vaccine efficacy trials. Subjects were randomly assigned to receive 100 providing long-term protective I-1g or 500 I-1g of vaccine or alum placebo, and were given three injections at immunity against multiple worldwide an accelerated 0, 1, and 2 month schedule. The vaccine was well tolerated subtypes of HIV and establishing with no significant local or systemic reactions observed in any subjects. international capabilities for large­ Fifty-five percent (100 I-1g dose) and 64% (500 I1g dose) of subjects who re­ scale efficacy trials of the most ceived the vaccine produced binding antibody to the immunogen as deter­ mined by EUSA. However, HIV-1 (MN) neutralizing antibody was detected in promising vaccine candidates. I It is only 23% (3/13) of subjects with detectable HIV-1 specific binding antibody. anticipated that extensive field It was concluded that this prototype HIV-1 synthetic peptide vaccine was I evaluation of any HIV vaccine can­ well tolerated, safe and immunogenic, and that a 0, 1, 2 month schedule was didate will involve populations in not as effective in stimulating HIV-1 specific neutralizing antibodies com­ pared with previous trials utilizing a 0, 1, 6 month schedule. Finally, this developing regions ofthe world where trial demonstrated that well-designed HIV vaccine trials can be performed at the HIV epidemic is most severe. 2 In this clinical trials site in Yunnan, China, and that this site should be consi· I this regard, public health agencies dered for conducting larger safety, immunogenicity and efficacy trials of including the World Health Organi­ candidate HIV vaccines. 1 zation3 and the National Institutes of Health4 have begun identifying poten_ I tial international sites for field evalua­ tion ofHIV vaccines. centers forming the National Institutes From the Ministry of Public Health, Temple of of Allergy and Infectious Diseases Heaven. Beijing. China; County Health and (NIAID) AIDS Vaccine Clinical Anti-Epidemic Station. longchuan. Yunnan, I China; Hua Yi Biotechnology Co. ltd., Bei­ 1 In the USA, most clinical ex­ Trials Network. 5 Many developing jing, China; Califomia Department of Health perience in the conduct of HIV vac­ countries have already recognized that Services, Berkeley, CA. USA; Prefectural Health and Anti-Epidemic Station. Mangshi, cine trials has been acquired through Phase IIII clinical trials of candidate Yunnan, China; AIDS Department. Provincial the repeated perfonnance of smalJ HIV vaccines in their own populations Health and Anti-Epidemic Station. Kunming, I Yunnan, China; and United Biomedical. Inc. ~ Phase I and Phase II clinical trials are likely to provide the most relevant Hauppauge, NY, USA with candidate vaccines at specific information and experience for Correspondence: Wayne C Koff 106 U, ET AL.

consideration of future large-scale munogenic and safe, with no sig­ fying 774 confirmed HIV-l . efficacy trials.6 In preparation for nificant adverse events attributable to Of these, 743 (95%) of all infections II conducting international efficacy trials the vaccine being reported. ,12 Based were in Dehong prefecture, with the using a multicomponent HIV vaccine, on these preliminary findings, this principal risk factor being injecting United Biomedical, Inc. (llBfY) in prototype HIV-1 vaccine became the drug use (82%), followed by pros­ cooperation with a network of inter­ first vaccine endorsed by the WHO titution (13.3%). In 1992, of 277 national clinical investigators from Global Programme on AIDS Steering randomly screened injecting drug Asia, Afiica, South America and the Committee on Vaccine Development users (!DU) in Longchuan county, United States, has developed a clini­ for evaluation in developing countries. 119 were confirmed HIV -1 positive cal research program to provide the (43.5%), an increase of 8.2% over a essential experience in the conduct of The purpose of this present similar survey in 1990. 13 HIV-1 virus HIV vaccine trials in the proposed tar­ study in China was to extend the isolations from Yunnan, China have get populations. This program in­ evaluation of the prototype HIV-l included multiple intraclade B isolates cludes the development ofmethods for synthetic peptide vaccine using an (eg. Divergent North American and recruitment, counselling, informed accelerated immunization schedule, Thai B) and clade C subtypes which consent, and clinical practice con­ and to develop the social, political, reinforces the importance of deve­ sistent with the accepted codes of and clinical trials infrastructure at the loping HIV vaccines capable of pro­ Good Clinical Practice, and to develop Longchuan site for future HIV tecting against variable subtypes of the laboratory and clinical infra­ vaccine field trials in IDU popula­ HIV.I4-16 structure necessary to perform HIV tions at higher risk for HIV infection vaccine clinical trials in less developed in Yunnan, China. Study approvals regions. These studies build on the existing local, social, political, and Approval for the Phase I cli­ METHODS clinical infrastructure to develop a nical trial ofthe UBI candidate HIV-l locally adapted process applicable to vaccine was obtained from the site and study pop­ the region and its population. Ministry of Public Health of the ulation People's Republic of China, fol­ lowing review of preclinical data, and The prototype HIV-1 vaccine The study site comprised the preliminary safety and im­ used in the study reported here is a town and county of Longchuan, De­ munogenicity data obtained from monovalent HIV-1 synthetic peptide hong prefecture, in Yunnan province, Phase 1 studies performed in the vaccine based on the clade B, MN China. Longchuan is a rural county USA Approvals for the clinical trial sequence which overlaps a portion of of 150,000 residents located adjacent were also obtained from the the HIV -I principal neutralizing to the border with Myanmar, in what governments of the Yunnan province, determinant (PND) of the V3 loop.7.9 is commonly known as the "Golden Dehong prefecture and Longchuan In preclinical studies, this immunogen Triangle". It is estimated that there county. demonstrated the capacity to stimulate are approximately 4,000 drug users in long-term high titer neutralizing the county, and as a result of this high Subjects antibodies directed against HIV,8.9 and number, local authorities implemented mixtures of similar immunogens re­ a comprehensive HIV-I surveillance The volunteer subjects for this presenting different subtypes of HIV program as part of a national sur­ study were drawn from villages were capable ofboosting humoral and veillance program. This was achieved located within 20 km of Longchuan cellular immune responses of a through the establishment of 29 out­ town. Subjects were HIV-negative, recombinant poxvirus vaccine expres­ post surveillance centers for coun­ healthy adults engaging in higher risk sing HIV gp 160 to sufficient levels to selling and HIV testing of higher risk behavior for HIV infection as confer protection against subsequent individuals throughout the province. determined by interview questions, virus challenge. 10 This prototype HIV­ who fully understood the purpose and 1 MN synthetic peptide vaccine has Between 1989 and 1992, 88,965 details of the study, and gave their previously been evaluated in the subjects in Yunnan province were written informed consent. Eligibility United States, and found to be im­ screened for HIV-1 infection identi­ for the trial was dependent on results HIV-1 PEPTIDE IN CHINA 107

of physical examination and a health regimen: 12 subjects received the 100 Counselling and lifestyle review. Table I describes J.tg dose; 12 subjects received the 500 All subjects received coun­ the inclusion and exclusion criteria for J.tg dose; and 5 received placebo. One seling prior to their enrollment, and the clinical trial. On initial screening, male IOU subject died on day 25 of throughout the course of the study. 30 subjects were found eligible for the study in a lifestyle related event Counselling was required to assist the enrollment into the study. This group not attributable to vaccine or vac­ subjects with developing a complete comprised 26 male and 4 female cination as determined by the Long­ understanding of the study procedures subjects, with all male subjects known chuan Department of Public Securi­ and the possible consequences. Spec­ to be IOU and with all four female ty, Health and Anti-Epidemic Sta­ ific counselling was necessary before subjects being sexual partners of four tion. subjects agreed to lllV antibody male subjects. The et1mic distribution testing. Information and education All subjects were IDV -I sero­ of the first 30 subjects initially was provided to subjects on risk negative using a diagnostic kit (UBI enrolled were as follows: 15 Chinese; behavior changes and ways to make IDV-l EIA) licensed by the U.S. Food 13 Jingpo; and 2 Dai. Due to the and sustain these changes throughout and Drug Administration (FDA) and withdrawal of 8 Jingpo subjects the study. Counselling was made all were Mantoux (PPD) test negative. following trial commencement for available to subjects at any time Three subjects tested positive for personal reasons, an additional 8 during the study. Chinese male volunteer subjects were antibody to hepatitis C virus, but subsequently recruited from a regional remained eligible as this does not form Synthetic peptide candidate mV-l vaccine voluntary drug rehabilitation center. one of the exclusion criteria due to the A total of twenty-nine (29) subjects very high prevalence of HCV The prototype vaccine was completed the full three irrununization infection in IOU in this region.17 synthesized and formulated at United

Table 1 Subject inclusion and exclusion criteria for UBI® HIV-1 MN peptide prototype vaccine clinical trial, China

A. INCLUSION CRITERIA C. EXCLUSION CRITERIA

1. Age: 18 and 50 1. Active tuberculosis 2. Sex: Male or female 2. History of immunodeficiency, chronic illness, A negative pregnancy test at time of entry autoimmune disease or use of immunosup­ and assurance that adequate birth control pressive medications measures for duration of the study were 3. Evidence of psychiatric, or medical problems required for a/l female subjects during the previous six months which the 3. Normal history and physical examination investigator believed would adversely affect 4. Negative ELISA for HIV-1 the subject's ability to participate in the trial, 5. Availability for 16 weeks of follow-up or other responsibilities which would prevent 6. Either a history of injection drug use in the completion of participation in the study previous 12 months, or sexual behavior of 4. Prior receipt of an HIV vaccine higher risk 5. Pregnant or lactating women

B. SUPPLEMENTAL INCLUSION CRITERIA

1. S.,xually transmitted disease in the previous six months 2. Receipt of blood or blood products in the previous six months 3. Positive circulating hepatitis B surface antigen 4. Positive for hepatitis C virus antibody 108 L1. ET AL.

Biomedical, Inc., and consisted of HIV infection using the UBI HIV-I tralization assay using the HIV-1 MN eight homologous peptides EIA diagnostic test. This ELISA test laboratory strain, grown in MT-2 corresponding to the gp 120 principal permits the discrimination between an cells, and using plaque reduction as an neutralizing domain of HIV-1 MN immune response to naturally­ indicator of reactivity.20 Neutraliza­ (amino acid residues 295-325) linked acquired HIV-I infection from that tion titers are reported as the reci­ to a heptalysyl core to form a radially induced through ,18 by procal of the serum dilution which branched structure by modification of targeting HIV-1 specific epitopes not yields a 50% reduction of plaque the Merrifield solid-phase procedure included in the prototype vaccine. The counts compared with control sera. for peptide synthesis.8.9 ability to distinguish natural infection from seroconversion induced by a RESULTS The peptide immunogen was candidate HIV vaccine based on viral purified to greater than 95% by high envelope proteins or peptides, is Demographic data and clinical pressure liquid chromatography, and considered an important prerequisite safety evaluations formulated using water for injection to the evaluation of candidate HIV into a phosphate buffered saline vaccines in developing countries. 19 Table 2 summarizes the de­ (PBS) solution employing aluminum mographics of the study population. hydroxide gel as adjuvant at a final SUbjects were observed for one It was necessary to enroll thirty-eight concentration of 0.2%. Thimerosal hour post-vaccination, and vital signs (38) subjects to assure that twenty was used as an anti-microbial and any reactions were assessed by nine (29) subjects completed the entire preservative at an effective concen­ the clinical staff at the end of this immunization sequence. This was due tration of 0.01%. The placebo con­ observation period. At 6 hour and 12 to the voluntary withdrawal of eight trol consisted of 0.2% aluminum hy­ hour time points, the subjects recorded Jingpo subjects prior to the second droxide gel in PBS with thimerosal their temperatures and any symptoms vaccination following the drug-related (0.01 %) included as preservative. All they experienced in a personal diary death of a male Jingpo subject (see vaccine and placebo doses were provided. Final protocol-follow-up Methods). The 29 subjects consisted supplied in coded, single dose vials, occurred two months after the of 25 males and 4 females, with a with all local investigators and sub­ administration of the final vaccine mean age of 27.2 years. The ethnic jects remaining blinded to vaccine dose (at 20 weeks) but subjects demography of the group was: 23 dose and placebo. The treatment code continued to be monitored as part of Chinese, 4 Jingpo, and 2 Dai. The was retained at UBI, Hauppauge, NY, the routine community health program demographic characteristics of the USA and was released to the study in the region. trial were not significantly different site investigators upon completion of among the vaccine groups. the study. Immunogenicity detenninations The vaccine was found to be Vaccination and follow-up safe, and was well tolerated by the Evaluation of HIV-I peptide subjects (Table 3). Following vacci­ All subjects were randomized to binding and virus neutralizing anti­ nation, the majority of subjects exhi­ one of three study groups, to receive body was determined by the fol­ bited either no symptoms or mild three doses of either 100 IJg or 500 lowing algorithm. All samples were symptoms, with no significant dif­ iJg of study vaccine, or placebo, on a initially screened by ELISA for ferences among vaccine groups. No 0, 1, 2 month schedule which was binding antibody to the homologous severe pain or tenderness was re­ administered by intramuscular HIV-l MN PND peptide octamer.8.9 ported at the injection site following injection in a 0.5m1 volume. All ELISA responses are presented as the the first, second, or third injection. subjects were vaccinated either at the highest serum dilution giving an These findings were comparable to Longchuan Health and Anti-Epidemic ELISA absorbance of at least 0.2 plus those observed in studies previously Station in Longchuan town, or at their background. A positive ELISA result conducted in the United States. 1l.12 village for subjects at more remote was defined by an ELISA absorbance locations. All subjects were monitored value of 0.2 plus background at a Binding antibody detenninations throughout the study for local and 1:31 dilution. ELISA positive sera systemic adverse reactions, and for were screened in a standard neu­ Post vaccination serum was HIV-1 PEPTIDE VACCINE TRIAL IN CHINA 109

Fig. 1. No HIV-1 antibody responses

Table 2. Demographic characteristics of subjects for Lon9chuan HIV-1 were detected in any of the subjects vaccine clinical trial who received all three doses of placebo (Group I). Serum antibody responses were observed in both the Group 1 Group 2 Group 3 Total 100 /J8 and 500 /J8 groups beginning Vaccine Placebo 100 119 500 119 at week 12. By week 16 (eight weeks following the third immunization), Numberl 5 12b 12c 29 6/11 subjects who received the 100 /J8 dose were positive by HIV-I PND 24.8 26.3 29.2 27.2 Mean age (yrs.) specific ELISA (GMT= I :93, Male 5 11 9 25 range=I:33-1:214) and 7/11 subjects who received the 500 ~g dose Female 0 3 4 (GMT=I:74; range=I:37-1:283).

a Indicates the number of subjects who received the full course of at 0,1,2 months; Note that 9 other subjecls received an immunization at Day 0; 8 withdrew Ibr personal reasons belbre the Neutralizing antibody detennina­ second immunization; 1 subject died of a suspected IOU related death independent of the vaccine or vaccination on day 25 of the study tions b One subject withdrew after completing the three immunization regimen Ibr personal reasons C One subject withdrew post third immunization due to a family emergency Serum which scored positive by HIV-1 PND specific ELISA was evaluated for HIV specific neu­ tralizing antibody (Table 4). Three of Table 3. Local and systemic clinical reactions 13 sera demonstrated detectable HIV specific neutralizing antibody versus the HIV-MN strain, which contains Placebo 100 119 500 119 amino acids of the V3 loop of the Total number of subjects 8 15 15 envelope glycoprotein gp120 homo­ I. Visible reactions logous to the prototype vaccine. Neu­ at injection site tralization titers ranged between 1:20 Post 1st vaccination 0 2 0 and I: 100. By comparison, 90% of Post 2nd vaccination 0 2 1 Post 3rd vaccination 0 1 1 subjects receiving this immunogen on II. Pain and tendemess a 0, I, 6 month schedule produced at injection site neutralizing antibodies with titers Post 1st vaccination 1 2 0 ranging from 1:19 to 1:355 in a Phase Post 2nd vaccination 0 2 1 1 trial conducted by the NIAID AIDS Post 3rd vaccination 0 1 1 III. Systemic symptoms Vaccine Clinical Trials Network,12 Post 1st vaccination 0 0 1a and 95% of volunteers immunized Post 2nd vaccination 0 0 0 with the 0, I, 6 month schedule eli­ Post 3rd vaccination 0 0 0 cited neutralizing antibodies with titers a Muscle soreness, dizziness, and nausea. ranging from I: 14 to 1:1,294 in a trial conducted with the Thai Red Cross Pro-gram in Bangkok, Thailand?1 available from 27 of 29 subjects who 20. Another subject withdrew and received all three . One returned to his home province due to a DISCUSSION subject withdrew from the trial family emergency and was not following the complete series of im­ available to provide post-vaccination This study in Longchuan, Chi­ munizations for personal reasons, and sera on weeks 16 and 20. The HIV-l na, demonstrated the feasibility of was not available to provide post­ PND-specific antibody responses as conducting HIV vaccine clinical trials vaccination sera for weeks 12, 16, and measured by ELISA are presented in in a developing region, by building on 110 LI. ET AL.

Binding Antibody to HIV-1 V3 Branched Peptide by EIA

100 0 100J1g dose group 500J1g dose group 80 • Q) 1 Vaccination :p> 74 (/) 0 60 0... cfl 40

20

0 0 4 8 12 16 20 1 1 1 Week of Study

Fig. 1. Binding antibody to HIV-1 V3 branched peptide by EIA. EIA assays conducted as described in Methods. Figure shows the percent samples positive over the number tested for both the 100 Ilg and 500 jJ.g dose groups. Sera from placebo recipients were negative on the HIV-1 V3 branched peptide EIA at all time points. Values above the bars indicate geometric mean titers (GMl). Range of titers for week 16 samples are shown in Table 4.

Table 4. HIV-1 binding and neutralizing antibody determinations

Dose Subjects Anti-V3 EUSAa Neut. Ab-MNb

100 Ilg 11 6/11 2J6 (1:33-1:214) (1:20-1:100)

500 Ilg 11 7/11 1n (1:37-1:283) (1:72)

• Values indicate number positiveInumber tested at v.,oeek 16 ofllle study (8 v.,oeek pastille third immunization); Range of titers indicated in parentheses. b Values indicate number positiveInumber tested. Note thai only ElISA positiw sera were evaluated for neulralizing antibodies. Range oftiters indicated in parentheses. HIV-1 PEPTIDE VACCINE TRIAL IN CHINA 111

eXIstIng social, political and epide­ shorter schedule was intended to belonging to the Jingpo ethnic miological/public health services. The provide an opportunity to determine if minority and known to be an active region had already established an open biologically relevant antibody res­ intravenous drug user was found IDV surveillance program based on a ponses could be induced at an earlier dead, and the provisional diagnosis of network of field stations in colla­ time point than has been observed, sudden unexplained death was noted boration with the central and regional since the long vaccination schedules by the local physician. This diagnosis governments. In recognition of the over many months may not be was a frequent diagnosis of young severity of the IDV epidemic in the appropriate in the setting offield trials male drug users within this com­ populations of this region, these in a developing region with high munity, and was confirmed by further agencies have implemented local incidences of IDV infection. The inspection as determined by the education and counselling programs. choice of 0, 1, and 2 months was Longchuan Department of Public However, despite these efforts in derived from previous successful Security, Health and Anti-Epidemic AIDS education, IDV continues its studies with accelerated schedules Station. Following the drug-related insidious spread in this region, re­ with recombinant hepatitis B surface death ofthe male Jingpo subject, eight inforcing the need for the development antigen vaccine,26 and provided an additional Jingpo subjects voluntarily ofa safe and effective vaccine. During opportunity for a direct comparison withdrew from the trial prior to the the five months of preparation from with an IDV gp 160 vaccine pre­ second vaccination for personal and time of approval to implementation of viously evaluated on both a standard religious reasons. After consultation this study, additional education was and accelerated schedule. 27 with local representatives conducting provided to the local population in the clinical trial, a decision was made order to establish a satisfactory level The present study has to recruit additional subjects to of understanding of the clinical trial demonstrated that while IDV -I spe­ complete the enrollment ofthe trial. process ofIDV vaccine development. cific binding antibody can be induced by this accelerated schedule in ap­ The prototype vaccine eva­ proximately 60% of subjects, only Incidents unrelated to vaccine luated in this study had previously 23% of subjects eliciting binding or vaccination such as the one des­ been evaluated in the United States in antibody were capable of inducing cribed can have a significant impact subject groups at lower and higher IDV -I specific neutralizing antibody. on the ability to successfully conduct risk for IDV infection under an FDA These observations indicate that the clinical trials, if not handled appro­ Investigational New Drug (IND) accelerated schedule is less effective in priately and professionally. The application prior to its evaluation in stimulating neutralizing antibody than Longchuan Department of Public China. It has also been evaluated in the 0, I, 6 month schedule utilized in Security, Health and Anti-Epidemic Thailand, 21 Australian and is currently previous trialS. ll,I2,21 Similarly, studies Station, in consultation with clinical under test in Brazil. In the completed utilizing an IDV gp 160 comparing a associates conducting this Phase I U.S. and Thai studies, the vaccine has 0, I, 6 month schedule to an acceler­ trial, handled this incident in a highly been demonstrated to be safe, well ated monthly immunization schedule effective manner enabling the tolerated with minimal reactions, and suggested that lengthening of the additional recruitment to occur and without any systemic adverse events resting period between the second and completion of the clinical trial as. attributable to it. It has been shown to third immunizations led to more planned. induce both IDV -specific neutralizing potent and durable IDV specific im­ antibody and T-helper memory res­ mune responses.25,27 Although continued assess­ ponses. 11 ,12,21 ment of safety and immunogenicity of Finally, the death of a volun­ this prototype vaccine was an The 0, I, and 2 months vacci­ teer by a lifestyle related event not important goal of this study, the key nation schedule used in this study attributable to vaccine or vaccination, accomplishment was the establish­ differed from the 0, I, and 6 month in this initial IDV vaccine trial in ment of the infrastructure within used in other studies with this UBI® China, provided an opportunity to China for the meaningful evaluation prototype HIV vaccine and com­ address the public health infrastruc­ of next generation candidate IDV monly used with other subunit IDV-l ture associated with vaccine trials in a vaccines. We have been able to de­ vaccine candidates. 2J.25 The use of the developing country. One male subject monstrate that where there is a poli­ 112 LI. ET AL

tical will to collaborate in a develop­ port of Professor Chen Minzhang, 5. Walker MC, Fast PE. Clinical trials of ment program targeted at generating a Minister of Public Health, People's experimental AIDS vaccines. AIDS 1994; safe and globally effective HIV Republic of China, for facilitating this 8 (supp11): 213-26. vaccine, the experience gained is likely collaborative clinical trial, and 6. Global Programme on AIDS. Statement from the consultation on criteria for in­ to significantly shorten the time frame appreciate the contributions of He ternational testing of candidate HIV vac­ for development and eventual delivery Lianmei, Vice Governor, Longchuan cine. World Health Organization: Gene­ of the vaccine. In this regard, addi­ County Government, China; Yang va, Switzerland. February 27-March 2, tional Phase I studies have now been Enjiang, Vice-Director, Longchuan 1989. undertaken in multiple sites both in the Government Office, China; Zhao 7. O'Hagan DT, McGee JP, Wang CY, Potts B, Koff WC. The UBI multicom­ U.S. and abroad, in preparation for Zhongwen, Director, Longchuan ponent HIV vaccine; the advantages of efficacy trials of a final IDV vaccine Bureau of Public Health, China; Cha controlled release microparticles. Se­ candidate. While the difficu1ties in Juling, Vice-Director, Longchuan venth Colloquium of Cent Gardes. Paris, con-ducting studies in less developed Health and Anti-Epidemic Station, France 1993; pp. 309-13. 8. Wang, CY, Looney OJ, Li ML, et al. regions of the world must not be un­ China; Liu Huan, Provincial AIDS Long term high titer neutralizing activity derestimated. it is important that these Office, Kunming, China; Wang induced by octameric synthetic HIV -I challenges are not overstated such that Zheng, Hua Yi Biotechnology Co., antigen. Science 1991; 254: 285-8. they paralyse the process of conti­ Beijing, China; Rosanne Boyle, Lloyd 9. Walfield AM, Li ML, Ye J, et. al. In­ Dodge, Keith Field, Diana Gumaer, duction of high titer persistent neutral­ nuing HIV vaccine development,28 izing antibodies by HIV-I V3 octa­ When an IDV vaccine has demon­ Steve Kaminsky, Barbara Potts, branched peptides. In: Chanock RM, strated in Phase IIII safety and im­ Ramona Lione, United Biomedical, Ginsberg HS, Brown, F, and Lerner, RA munogenicity trials the capacity to Inc., Lynette Sawyer, Leo Oceguera, (eds). Vaccines 92. Modern Approaches Mary Kate Morris, Gary Tam, Cali­ to New Vaccines Including Prevention stimulate both humoral and cellular of AIDS. Cold Spring Harbor Laborato­ immune responses in a significant fornia Department of Health Ser­ ry Press: Cold Spring Harbor, NY. 1992: majority of volunteers, including vices, Berkeley, California; and the 211-5. neutralizing antibodies against diver­ clinical and laboratory staff of 10. Abimiku AG, Franchini G, Tartaglia J, et gent IDV subtypes, IDV-specific T­ Longchuan Health and Anti-Epide­ al. 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