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Phase II Clinical Trial of HIV Therapeutic Optimized DNA Vaccine: Viral Reservoir Reach

This report discusses the results of a Phase II clinical trial on an HIV therapeutic optimized DNA vaccine, focusing on the possible reach of viral reservoirs. The study includes detailed information on the vaccine composition, production process, and immune response development. Safety and efficacy data from preclinical and Phase I trials are also presented.

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Phase II Clinical Trial of HIV Therapeutic Optimized DNA Vaccine: Viral Reservoir Reach

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  1. The Results of Phase II Clinical Trial of HIV Therapeutic Optimized DNA Vaccine: The Possible Reach of Viral Reservoirs Kozlov Andrei The Biomedical Center and Research Institute of Pure Biochemicals, St. Petersburg, Russia INTERNATIONAL CONFERENCE  "TOOLKITS FOR DNA VACCINE DESIGN, AN UPDATE" Moscow, November 17-21, 2016

  2. Confirmation of the first cases of HIV infection in St.Petersburg in 1987 Kozlov et al., 1987

  3. CRF03-AB F 98BY10443 K 03-AB.KAL153 03-AB.98RU001 C B H D J A2 98UA0116 G A.97BL006 A-FSU A1 The full-length genome phylogeny for the predominant in Russia HIV-1 genetic variants A-FSU and CRF03-AB

  4. HIV-1 genome (consensus sequence of the FSU subtype A HIV-1 variant) GAG POL ENV NEF LTR LTR accessory genes gag rt gp140 nef p7 p17 p24 prot RT int gp120 gp41 p15 vif vpr tat vpu p6 DNA-4 vaccine contained an equimolar mixture of four plasmids insaline solutionwith an overall concentration of 1 mg/mL Study Product

  5. control control w.t. nef w.t. gag syn. gag syn. nef 1/1 syn. nef 1/50 syn. nef 1/10 33kDa 72kDa 54kDa 24kDa Nef Gag Expression of wild-type and “optimized” HIV-1 genes in 293T cellsin vitro

  6. Large-scale Production of Plasmid DNA Protein precipitation with ammonium acetate Plasmid DNA precipitation with isopropanol Alkaline lysis and KOAcprecipitation Plasmid DNA precipitation with PEG 8000 Fermentation RNA Sephacryl S1000 А260 SC plasmid DNA DNA E.coli Quality control, immunization Plasmid DNA E.coli DNA 3% 8% 10% OC Fraction Column purification Concentration and Diafiltration SC

  7. Quality Control of DNA Vaccines Purified by Chromatography

  8. CTL-analysis 8 E:T 10:1 lysis E:T 20:1 6 E:T 50:1 (minus control), % 4 Specific 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time ( weeks ) CD8 analysis CD8+, IFN+ (minus control), % CD4 analysis CD4+, IFN+/IL4+ (minus control), % Time Time ( ( weeks weeks ) ) boost boost Immune Response Development After Three Serial i.m. Injections of the DNA Vaccine

  9. Results of preclinical trials of the candidate DNA vaccine • DNA vaccine was not toxic for laboratory animals in acute toxicity experiments and corresponded to the 5th class of practically non-toxic substances. • Lethal doses LD50, LF16 and LD84 were impossible to estimate. The highest administered doses were 4 orders of magnitude higher than the proposed immunization dose. • DNA vaccine had no allergenicity. • DNA vaccine was not toxic after chronic administration in rats and dogs. • DNA vaccine had no pyrogenic effect. • Efficient stimulation of vaccine specific CTL, CD8+ IFNγ+ lymphocytes and induction of Th1 response were observed after the i.m. priming.

  10. Study Schema of Phase I trial of a prophylactic HIV-1 DNA-vaccine in St. Petersburg, Russia Demographics

  11. Pools of overlapping peptides Peptides - 15 aa overlap - 11 aa

  12. Immune reactivity

  13. Results of Phase I Clinical Trial • DNA-4 vaccine is well tolerated. • Vaccination with DNA-4 regimen elicited moderate CD4+ and CD8+ T-cell responses, but modest humoral responses. • This regimen should be considered as part of future vaccine strategies. • 0,25 mg dose of DNA-4 is enough to induce immune responses. • 100% immune reactivity of trial participants

  14. TNFa is produced both in ESN and DNA vaccine trial participants CD3+CD8+ CD3+CD4+ Nef-pool Nef-pool * * * * % CD3+CD8+ % CD3+CD4+ * * Gag-pool Gag-pool * * % CD3+CD8+ % CD3+CD4+ * * * - Average in group, - Average negative control, * р<0.05 Mann-Whitney U-test between examine group and negative control ICS The correlation in TNFa production with that in ESN individuals may a promising indication for the possible efficacy of our candidate DNA vaccine.

  15. The Study Shema of Phase II Clinical Trial of the Therapeutic HIV-1 DNA Vaccine Double-blind, placebo controlled trial 11 7 15 Days of vaccination 1 Follow-up to 24 weeks (6 visits) 8 AIDS Centers

  16. The safety estimates X – число пациентов с НЯ, % – процент пациентов с НЯ; Y – число НЯ • No death cases • No serious unfavorable events

  17. Unfavorable events Зарегистрированные НЯ в исследовании, встречающиеся у ≥ 1 пациента (классификация НЯ по DAIDS, версия 1.0 )

  18. Laboratory parameters ОТКЛОНЕНИЯ ЛАБОРАТОРНЫХ ПОКАЗАТЕЛЕЙ, ЭКГ • При анализе отклонений лабораторных показателей особое внимание уделялось мониторингу основных параметров безопасности, которые наиболее чувствительны при лечении ВИЧ инфицированных пациентов: - оценке изменения абсолютного числа СD4+ лимфоцитов, - лейкоцитов крови, - абсолютного числа нейтрофилов крови, - гемоглобина, АЛТ, АСТ. No difference in laboratory parameters was found

  19. Safety conclusion DNA-4 vaccine is safe and well tolerated at the doses 0,25 and 0,5 mg in HIV-infected patients on HAART

  20. Dynamics of plasma virus levels

  21. The results of blips analysis The number of blips and the number of patients with blips are the same in control and trial groups

  22. The results of viral load analysis («blips») But in the study groups blips with higher level were observed

  23. Activation of proviral DNA and latent reservoir destruction may be connected with the expression of TNFα in vaccinated trial participants Exposed seronegative patients Phase I trial participants TNFa is produced both in ESN and DNA vaccine trial participants

  24. Заключение о возможной эффективности • Полученные результаты свидетельствуют, что терапевтическая ДНК-вакцинация, осуществляемая на фоне кАРТ, у ряда пациентов (2 из группы 0,25 мг и 1 из группы 0,5 мг) может приводить к разрушению латентных вирусных резервуаров, что сопровождается реактивацией провирусных геномов и/или освобождением латентных вирусных РНК, и что является указанием на терапевтическую эффективность вакцины у некоторых пациентов. • Необходимы дальнейшие исследования, чтобы выяснить, приводит ли ДНК-вакцинация (или повторная ДНК-вакцинация) на фоне кАРТ к полному освобождению от ВИЧ-1 (eradication) и уничтожению латентных вирусных резервуаров у некоторых пациентов.

  25. Conclusion about possible efficacy • Therapeutic DNA vaccine in some HIV-infected patients on HAART may lead to destruction of latent viral reservoirs which mayeventually lead to HIV eradication

  26. Collaborators Акулова Е.Б., Аль-Шехадат Р.И., Мурашев Б.В., Веревочкин С.В., Машарский А.Э., Назаренко О.В., Астанина М.С., Красносельских Т.В., Лиознов Д.А., Соколовский Е.В., Поддубный В.А., Зозуля О.В., Востокова Н.В., Караваева О.В., Козлов А.П.

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