Current Knowledge on TCell Responses in Vaccine Trials

Knowledge gained from analyzing T-cell responses in natural infections, as in HIV-1 infection previously described (above), has provided valuable insights into what is needed for vaccine design and vaccination schedules. Today, novel technological advances are being made, leading in turn to improved ways of measuring CD8+ T-cell responses. Increasingly, these responses are being tested for in animal models and clinical trials of new vaccines. Against HIV infection, much of the recent effort to derive efficacious prophylactic vaccines has focused on the design and development of recombinant poxviral- and adenoviral-vector vaccines. These have been used either singly or together, or in combination with plasmid DNA vaccines in prime-boost regimes [95, 118]. For example, many clinical trials have already been conducted in volunteers (total over 1800) with ALVAC candidate prophylactic vaccines. The latter are usually designed to express multiple HIV antigens, including gp120, gag, and pro (vCP205, vCP1521). An analysis of data from eight volunteer trials showed that no dose response for CTL development could be demonstrated with ALVAC-HIV, but that the number of immunizations and the vaccine dose were associated with the likelihood of developing CTL responses [89]. It was however impossible to distinguish the effect of either the number of immunizations or the vaccine dose on CTL responses, as these two study characteristics were highly associated with each other [89]. In a more recent clinical trial ofan ALVAC-HIV vaccine (vCP1452), both the chromium-release assay for T-cell cytotoxicity and the IFN-y ELISPOT assay gave similar results for HIV-specific CTL responses, and clearly these were shown to be higher (15-16%) in the regular-dose recipients than in the high-dose (about eightfold higher than the regular-dose) recipients (8%) [90]. This outcome suggests that high-dose ALVAC-HIV vaccines do not necessarily provoke higher CTL responses; moreover, recipients of the higher dose had greater local and systemic reactions. The value of the study is that it indicates the need for further studies to develop a highly immunogenic ALVAC-HIV vaccine in which vector and insert design are optimized, as well as ways to increase dosage without increasing reactogenicity.

Since the immune response to ALVAC-HIV vaccines is still relatively low, other vaccination strategies are being evaluated in clinical trials. For example, the immunogenicities of candidate plasmid DNA- and recombinant MVA-vectored HIV vaccines have been evaluated on their own and in a prime-boost regimen in seronegative volunteers [91, 92]. These vaccines contained a common immunogen, HIVA, which consists of HIV-1 clade A Gagp24/p17 proteins fused to a string of clade A epitopes recognized by CTLs. The IFN-y ELISPOT assay was applied to measure HIV-1 specific T-cell frequencies (see Section 6.3.1.1). Encouragingly, the DNA and MVA vaccines alone and the DNA prime-MVA boost stimulated CTL responses in 14/18, 7/8, and 8/9 volunteers, respectively [91], and have also been shown to be safe [93]. Phase I/II trials with this and other recombinant MVA vaccines, mostly in prime-boost regimens, are continuing [94, 95], but overall in terms of CTL responses, with less than 35% of vaccinees scoring positive in the

IFN-y ELISPOT test at any one time, the immunogenicity of the current poxvirus-based HIV vaccines has been modest. Better results have recently been achieved with recombinant adenoviral vectored HIV vaccines in nonhuman primates and human volunteers [96-99]. Over 50% ofvolunteers receiving a monovalent Ad5-g»g vaccine developed longlasting HIV-1-specific CTL responses to HIV-1 peptides, as determined by cytokine production. A trivalent recombinant Ad5-gag/pol/nefhas been recently developed and is currently being trialled in volunteers, but results are not expected until 2008 (see Table 6.1) [95].

Although DNA-Ad5 and Ad5-poxvirus prime boost regimes are also being tested [119], pre-existing immunity to Ad5 may prove problematic, and this has led to investigations to develop candidate recombinant Ad-HIV vaccines based on less prevalent Ads, serotypes such as Ad6 and Ad35 [95, 100, 119]. Numerous other

Table 6.1 Prophylactic HIV-1 vaccines in clinical trials

Vaccinea)

Immunogenic entity

HIV-1 clade

T-cell responses/ Method

Ref.

DNA.HIVAa)

Gagp24/p17 plus clade A epitopes

A

CTL/IFN-y ELISPOT

[91-93]

MVA.HIVAa)

Gagp24/p17 plus clade A epitopes

A

CTL/IFN-y ELISPOT

[91-93]

ALVAC.vCP1452

Env-Gag-Pol-CTL epitopes

B

CTL/IFN-y ELISPOT; chromium release

[90]

ALVAC.vCP205

Env-Pro-Gag-CTL epitopes

B

CTL/IFN-y ELISPOT

[89, 113, 114]

Recombinant Fowlpox virus (rFPV)-HIV-Ba)

Gag-Pol

B

CTL/IFN-y ELISPOT

[115, 116]

DNA.pHIS-HIV-Ba)

Mutated Gag-Pol-Env-Vpu-Tat-Rev

B

CTL/IFN-y ELISPOT

[115, 116]

MVA.HIVC

Env-Gag-Tat-Rev-Nef

C

Under trial in India

[95]

MVA.HIVA/E

Env-Gag-Pol

A/E

Under trial in USA/ Thailand

[95]

Ad5.HIV-Gag monovalent

Gag

Codon-biased

CTL/IFN-y, IL-2 and TNF-a secretion

[95, 99, 119]

Ad5.HIV-trivalent

Gag-Pol-Nef

?

Under trial in several countries

[95, 99]

Ad5.HIV-multivalent

Env (A,B,C); Gag-Pol-Nef (B)

A,B,C

Under trial in USA, Brazil, South Africa

[95, 117]

a) Most of the candidate HIV-1 vaccines have been used in plasmid DNA-viral vector prime-boost regimens, as in the vaccine pairs indicated here. For clinical trials information, the recommended websites are http://chi.ucsf.edu.vaccines and http://www.iavi.org.

TNF = tumor necrosis factor.

nonreplicating viral vector-based HIV vaccines are in development as candidate preventative HIV-1 vaccines [102]. Of these, perhaps the one that shows most promise is that based on an attenuated VSV vector expressing the Gag and Env proteins. This was found to provide complete protection against CD4+ T-cell loss and disease progression in the SHIV/macaque model when, advantageously, the vaccine was administered intranasally [103, 104].

The use of poxvirus-based vectored vaccines is also finding favor for the development of preventive vaccines against other intracellular pathogens, such as malaria [105]. Immunization with plasmid DNA encoding malarial antigens followed by boosting with a recombinant MVA vaccine [106], a novel attenuated fowlpox virus [107], or a recombinant replication-defective adenovirus [108] expressing malarial antigens in animal models, has been shown to enhance CD8+ T-cell induction. Durable, protective memory T-cell responses have also been quantified by ELISPOT assays after such prime-boost vaccination regimes against malaria in human volunteers [109].

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