Vaccines for prevention of HIV infection

  • Protocol
  • Intervention

Authors

  • Ani Etokidem,

    Corresponding author
    1. University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria
    • Ani Etokidem, University of Calabar Teaching Hospital, Po Box 3124, Calabar, Cross River State, 540001, Nigeria. anietokidem@yahoo.com.

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  • Charles I Okwundu,

    1. Stellenbosch University, Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Tygerberg, South Africa
    2. South African Medical Research Council, South African Cochrane Centre, Tygerberg, Western Cape, South Africa
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  • Andrew Anglemyer

    1. University of California, San Francisco, Global Health Sciences, San Francisco, California, USA
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the efficacy and safety of vaccines for the prevention of HIV infection using phase 3 studies.

Background

Current HIV prevention strategies include a range of behavioural and biomedical interventions, as well as combinations of interventions. Among others, behavioural interventions include those to reduce sexual risk behaviour (Naranbhai 2011, Ojo 2011, Wariki 2012), interventions to improve uptake of HIV testing (Bateganya 2010, Vidanapathirana 2005, Wei 2011), and interventions delivered by telephone (van-Velthoven 2013). In addition to the correct and consistent use of condoms (Weller 2002), some key biomedical HIV prevention interventions include antiretroviral "treatment as prevention" (Anglemyer 2013) and pre-exposure prophylaxis (Okwundu 2012), antiretroviral prophylaxis for preventing mother-to-child HIV transmission (Siegfried 2011), male circumcision (Siegfried 2009, Wiysonge 2011), and the use of topical microbicides (Obiero 2012).

Many believe that a vaccine is the most promising way of ending the HIV epidemic. The first successful eradication of an infectious disease ever achieved in history was done using a vaccine (Fenner 1988). The features of an ideal vaccine include safety, cost, long shelf life, ease of administration and effectiveness.

Description of the intervention

A vaccine is a preparation of a weakened or killed pathogen, or a synthetic substitute of a portion of the pathogen's structure that upon administration stimulates antibody production or cellular immunity against the pathogen but is incapable of causing severe infection.

Vaccines are a cost-effective method of controlling infectious diseases (Stratton 2002). The successful eradication of smallpox using vaccines and the development of an effective vaccine against a HIV-related virus (i.e. feline immunodeficiency virus) (Mazzetti 1999, Yamamoto 2006), raised hope of finding a vaccine against HIV. Thus, substantial research effort is being spent on finding such an effective vaccine. One of the greatest challenges to developing a preventative HIV vaccine is the diversity of HIV-1 isolates. Envelope (Env) gene sequences can differ by as much as 35% between isolates from different clades and by as much as 10% within a clade (McBurney 2007).

The ability of HIV to integrate itself into the DNA of the host also poses a challenge to vaccine development (Johnson 2008). Presently, there are six types of experimental HIV vaccine (HVTN 2009) namely :

  1. Peptide vaccine: made of tiny pieces of proteins from the HIV virus

  2. Recombinant subunit protein vaccine: made of bigger pieces of proteins that are on the surface of the HIV virus. Examples of a recombinant subunit protein are gp120, gp140, or gp160 produced by genetic engineering.

  3. Live vector vaccine: non-HIV viruses engineered to carry genes encoding HIV proteins. The genes are inserted into another vector, which carries them into the body's cells. The genes in turn produce proteins that are normally found on the surface of the HIV virus. This type of vaccine most resembles the HIV virus but is not harmful. Many vaccines used today, like the smallpox vaccine, use this approach.

  4. DNA vaccine: uses copies of a small number of HIV genes which are inserted into pieces of DNA called plasmids. The HIV genes will produce proteins very similar to the ones from real HIV.

  5. Vaccine combination: uses any two vaccines, one after another, to create a stronger immune response. Often referred to as "prime-boost strategy."

  6. Virus-like particle vaccine (pseudovirion vaccine): a non-infectious HIV look-alike that has one or more, but not all, HIV proteins.

How the intervention might work

A preventive HIV vaccine would protect HIV-uninfected people from getting infected. When the human body encounters a microorganism, the person's immune system attacks the invading microorganism. If  it successfully overcomes the microorganism, the immune system continues to "remember" and to mount a defence against the microorganism the next time it enters the body. An HIV vaccine is designed to assist the immune system to recognize and attack the virus whenever it is encountered.

Research on HIV vaccines and prevention relies strongly on preclinical studies in macaque models for the identification and evaluation of potential vaccines or prophylactic treatment strategies (UNAIDS 2004). Animal trials are used to screen for preventive interventions that induce sterilising immunity. Unfortunately, most of the vaccine candidates so far tried have failed to induce sterilising immunity (Amara 2001, Barouch 2000, Rose 2001, Shiver 2002).

The complete inadequacy of the natural immune response against HIV is another challenge as is its inability to eradicate the virus once primary infection has been established. There is no documented case of spontaneous recovery from HIV infection. However, there are HIV-infected individuals who do not progress to AIDS as well as HIV-negative individuals who have been exposed to the virus multiple times suggesting that natural immune responses to HIV may be protective in rare individuals. Understanding the correlates of protective immunity to HIV infection is critical to efforts to develop preventive HIV vaccines as well as to determine the feasibility of treating HIV infection by boosting immunity to HIV (Haynes 1996).

There are reports of commercial sex workers who have remained uninfected despite frequent exposure to HIV. In such persons, HIV-specific mucosal antibody responses may exist and play a role in resistance against HIV (Dorrel 2000).

Demographic factors and genetic background of the human populations in HIV vaccine trials remain a source of potential variation in responses observed in such trials, yet empirical data remain limited on the impact of those factors. Coinfections, particularly those that may modulate the immune response, are a further concern for HIV vaccine trialists (de Bruyn 2010).

Why it is important to do this review

A number of clinical trials have evaluated the effectiveness of HIV vaccine candidates. These include the recently concluded (the world's largest) HIV vaccine trial, RV144 Phase III HIV Vaccine, among volunteers in Thailand, which tested a combination of two vaccines namely, ALVAC-HIV vaccine tagged "the prime" and AIDSVAX vaccine tagged "the boost" (Berkhout 2009). However, there has not been any published systematic review of vaccine trials. This review will collate the evidence to inform health care providers on the use of vaccines for the prevention of HIV infection.

Objectives

To evaluate the efficacy and safety of vaccines for the prevention of HIV infection using phase 3 studies.

Methods

Criteria for considering studies for this review

Types of studies

  • Only randomised controlled trials (RCTs) will be included in this review.

Types of participants

  • Sexually active HIV-uninfected adults (including men and women)

Types of interventions

  • HIV vaccine against placebo. Study participants should have access to other HIV prevention strategies (e.g., male or female condom or behavioural interventions).

Types of outcome measures

Primary outcomes
  • HIV infection

Secondary outcomes
  • Any adverse events associated with the vaccination, including severe (e.g. anaphylactic reactions, death).

Search methods for identification of studies

  • There shall be no language restriction in the search for studies.

Electronic searches

We will search the following databases, from 1 January 1980 to the search date:

  • Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library

  • MEDLINE

  • EMBASE

  • LILACS

  • CINAHL

Searching other resources

CONFERENCE PROCEEDINGS

To the extent that they are available, we will search archived conference abstracts for the Conference on Retroviruses and Opportunistic Infection (CROI), the International AIDS Conference (IAC), the International AIDS Society Conference on HIV Pathogenesis and Treatment (IAS), International Conference on AIDS and STIs in Africa (ICASA), from the earliest dates available until 2014.

RESEARCHERS, ORGANISATIONS AND PHARMACEUTICAL COMPANIES

Authors of HIV vaccine trials will be contacted for information on possible trials that may not have been published. Information on ongoing trials of HIV vaccines will be obtained from the web sites, www.clinicaltrials.gov, WHO trials register, ISRCTN (International Standard Randomized Controlled Trial Number Register). Organizations and agencies that promote and advocate for HIV vaccine development will be contacted such as AVAC, WHO, CDC, UNAIDS, USAID, UNFPA, FHI. Experts on HIV vaccines will be contacted for further information on trials and studies that may not have been identified. All pharmaceutical companies that develop HIV vaccines will be contacted for information and clarifications on published, ongoing and unpublished trials.

Searching other resources

Handsearches will be conducted. This is necessary because not all trials are included in electronic bibliographic databases and, even when they are included, they may not contain relevant search terms in the titles or abstracts or be indexed with terms that allow them to be easily identified as trials. We shall carry out handsearch of relevant journals or conference proceedings for all reports of relevant trials.

REFERENCE LISTS

We will also check the reference lists of all included studies.

Data collection and analysis

Selection of studies

Two authors (AE and CO) will independently screen the titles and abstracts obtained from the electronic searches and thereafter create a pool of eligible studies. Duplicate records of the same study will be removed. AE will obtain the full articles of the eligible studies. Two authors (AE and CO) will independently assess the studies using a standardised eligibility form with predefined inclusion criteria. Multiple reports of the same study will be linked together. Disagreements will be resolved by discussion between two review authors and, if necessary, by a third review author (AA). All excluded studies as well as reasons for exclusion will be listed.

Data extraction and management

Two review authors (AE and CO) will independently use a data extraction form specially designed for the review to extract data. Differences between review authors will be resolved by discussion or by appeal to a third review author (AA) if necessary. Information to be obtained will include:

  1. Details of the study including study location, settings, study design, sample size, total duration of study and attrition rate.

  2. Details of the study related to risk of bias, including sequence generation, allocation sequence concealment, blinding, and other concerns about bias.

  3. Details about study participants including age, sex, recruitment method, inclusion and exclusion criteria, socio-demographics, ethnicity, genetics, environmental factors (e.g. prior exposure to the vaccine vector, coinfection with other pathogens), number of sex partners, condom use, contact with commercial sex workers and other risk factors for HIV (e.g. migrant worker, truck driver, other STIs).

  4. Details about the interventions including number of intervention groups, description of interventions, duration of the intervention, method of delivery of the intervention, number and explanation for any dropouts and duration of follow-up and how loss to follow-up was handled.

  5. Details of study outcome including HIV infection and how HIV status was confirmed, mortality, any adverse events associated with the vaccination (e.g. anaphylactic reactions, death, abscesses, neuritis).The time points at which outcomes were noticed and reported will be noted.

  6. Details of study results, including number of participants allocated to each intervention group, missing participants, summary data for each intervention group, and details of any subgroup analysis conducted.

Assessment of risk of bias in included studies

The Cochrane Collaboration's Risk of Bias tool will be used independently by two review authors (AE and CO) to assess the risk of bias in the studies included in the review. Differences will be resolved by discussion or by appeal to a third reviewer (AA). The following criteria will be assessed:

  • Was the allocation sequence adequately generated?

  • Was the allocation adequately concealed?

  • Were study participants and treatment providers prevented from knowing the allocated treatment during the study?

  • Were outcome assessors prevented from knowing the allocated treatment during the study?

  • Were comparison groups similar at baseline?

  • Were incomplete outcome data adequately addressed ?

  • Are reports of the study free of suggestion of selective outcome reporting?

  • Was the study apparently free from other problems that may put the study at a risk of bias?

Results will be summarised in both a risk of bias graph and a risk of bias summary. Results of meta-analyses will be interpreted in light of the findings with respect to risk of bias.

Measures of treatment effect

For dichotomous outcomes (e.g. whether or not participants contracted HIV infection, death), results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes, e.g. CD4 count , Plasma Viral RNA load etc), the mean difference (MD) will be used, or the standardised mean difference (SMD) if outcomes were measured on different scales.

Unit of analysis issues

Studies with non-standard designs (cluster-randomised trials, cross-over trials and non-randomised studies) will not be included in this review.

Dealing with missing data

Authors of studies will be contacted for further information on missing data. Where this is either not possible or no further useful information is forthcoming, missing data will not be imputed.

Assessment of heterogeneity

Statistical heterogeneity will be assessed using three methods namely, visual assessment of the forest plots and using the χ2 and I2 statistics. Where heterogeneity is suspected, we will further investigate the possible sources of heterogeneity using sensitivity analysis, and/or subgroup analysis.

Assessment of reporting biases

Comprehensive search strategies have been formulated for this review in order to cater for reporting biases. Other strategies put in place to cater for this include removal of date and language restrictions. Funnel plots corresponding to meta-analysis of the primary outcome will be examined to assess the potential for small study effects such as publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random effects model, further meta-analyses will be performed using fixed effects models.

Data synthesis

We will conduct meta-analysis, if studies are judged to be sufficiently similar, using Cochrane's Review Manager software (RevMan 2012) and present results using the Mantel-Haenzel risk ratio. Where data are not available, we will give a narrative summary of study results. Data will also be presented using the GRADEpro software (Guyatt 2008).

When interventions and study populations are sufficiently similar across the different studies, we will pool the data across studies and estimate summary effect sizes using both fixed- and random-effects models.  We intend to compare the estimates from fixed- and random-effects models in an attempt to explore the influence of small-study effects on results of a meta-analysis with intra-study heterogeneity. Specifically, we will estimate the log (risk ratio) for each included study and use the inverse variance method to calculate study weights. The inverse variance method assumes that the variance for each study is inversely proportional to its importance, therefore more weight is given to studies with less variance than studies with greater variance. If the estimates between the two modelling approaches are similar, then we can assume effects from small-studies only slightly affect the intervention's summary estimate. If estimates from random-effects are qualitatively substantially more beneficial than fixed-effects estimates, we will investigate whether the interventions were more effective in smaller studies than in larger studies. If upon reviewing the methodologies of the included studies we conclude that the larger studies were more rigorous, we may consider presenting only results from larger studies in a meta-analysis. As such, we intend to explore potential methodologic reasons for those differences in fixed- or random-effects estimates.

We will summarise the quality of evidence for the studies separately for each outcome for which data are available in GRADE Summary of Findings tables and GRADE evidence profiles (Guyatt 2008).

Subgroup analysis and investigation of heterogeneity

We will perform the following sub-group analysis: duration of vaccination, baseline characteristics of participants such as sex, age, genetic and racial background, and occupation. Others shall include type of vaccine, dose restrictions, difference in sexual exposure and differences in risk grouping. We will stratify the analysis by type of vaccine e.g. subunit vaccine, DNA vaccine etc.

Sensitivity analysis

We will use both random effects model and the fixed effects model to determine the robustness of the conclusion arrived at the end of review.

We will also exclude studies at high risk of bias, that is, plausible bias that seriously weakens confidence in the results.

Acknowledgements

The authors acknowledge the Nigerian Branch of the South African Cochrane Center for sponsoring one of the authors (Ani Etokidem) for the RAP programme. Action for Sustainable Health (NGO), Calabar, Nigeria, is also acknowledged for allowing unfettered access to its library.

History

Protocol first published: Issue 2, 2014

DateEventDescription
28 January 2013AmendedConverted to new review format.

Contributions of authors

Etokidem conceived and designed the protocol. Okwundu and Anglemyer  provided methodological perspective and made  input into writing the protocol.

Declarations of interest

There is no known conflict of interest.

Sources of support

Internal sources

  • The Nigerian Branch of the South African Cochrane Centre,Calabar, Nigeria.

    RAP TRAINING

External sources

  • The South African Cochrane Centre, South Africa.

    RAP TRAINING

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