Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses

Abstract

Background: The impact of anti-vector immunity on the elicitation of insert-specific immune responses is important to understand in vaccine development. HVTN 055 was a 150 person phase I randomized, controlled HIV vaccine trial of recombinant modified vaccinia Ankara (rMVA) and fowlpox (rFPV) with matched HIV-1 inserts which demonstrated increased CD8+ T-cell immune responses in the heterologous vaccine group. The controls used in this study were the empty vectors (MVA and FPV).

Methods: Anti-MVA and anti-vaccinia neutralizing antibodies (NAbs) were measured and compared with cellular and humoral HIV-1-specific immune responses.

Results: Elicitation of anti-vector responses increased with increasing dose of MVA and up to 2 administrations. Further inoculations of MVA (up to 5) did not increase the magnitude of the anti-MVA response but did delay the anti-vector NAb titre decay. There was no evidence that the insert impaired the anti-vector response, nor that anti-vector immunity attenuated the insert-specific responses.

Conclusion: Two doses of MVA may be ideal for the elicitation of orthopoxvirus immune responses with further doses maintaining increased titres against the vector. We found no evidence that eliciting HIV insert- or MVA vector-specific immune responses interfered with elicitation of immune responses to the other.

Trial registration: ClinicalTrials.gov NCT00083603.

Figure 1. Neutralizing antibody (NAb) titres to MVA and VACV are elicited in a dose-dependent manner among responders

Serum samples were obtained at days 0, 14, 42, 98, 154, 210, 273, and 394 following immunization. Serial dilutions were tested for neutralizing activity against (A) MVA:Luc or (B) VACV:Luc. Data are presented as median ID₅₀ titres with interquartile ranges (IQR) for each dose and immunization group. The limit of detection was a serum ID₅₀ titre of 10 and arrows indicate days of immunization. A positive response was defined as a titre ≥ 2 times the day 0 titre and ≥ 1:20.

Figure 2. The magnitude of anti-vector NAb responses has little impact on the magnitude of HIV-1 cellular immune responses by rMVA-HIV among vaccinees

The magnitude of HIV-1 specific CD4+ T cell responses among responders detected by intracellular cytokine staining (ICS) were compared with (A) anti-MVA and (B) anti-VACV NAb titers for NAb responders at days 42, 98, and 154. The magnitude of HIV-1 specific CD8+ T cell response among responders detected by ICS (C) were compared with anti-MVA (left) and anti-VACV (right) NAb titers for NAb responders at day 154.