Yellow fever vaccine for patients with HIV infection

  • Protocol
  • Intervention



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

To assess the risk and benefits of yellow fever vaccination for people infected with HIV.


Yellow fever (YF) is an acute viral haemorrhagic disease prevalent in tropical Africa and Latin America (WHO 2013a). The World Health Organization (WHO) estimates that there are 200,000 cases of YF and 30,000 deaths worldwide annually. Treatment for YF is supportive, but a live attenuated virus vaccine is effective for preventing initial infection (WHO 2013b). WHO recommends immunisation for all individuals >9 months living in countries or areas at risk (WHO 2013a). However, in the United States of America the Advisory Committee on Immunization Practices (ACIP) advises that YF vaccine is contraindicated in individuals with HIV, although these recommendations are primarily aimed at Americans travelling to endemic areas (CDC 2010).

Presently, more than 35 million people are infected with HIV (UNAIDS 2013). In 2013, UNAIDS reported that about 25 million people living with HIV reside in sub-Saharan Africa, while 1.5 million people living with HIV reside in Latin America, both largely tropical, often densely populated regions where YF is endemic (UNAIDS 2013). Given this context, YF vaccine may be an important intervention for preventing YF in HIV-infected persons.

While YF vaccine is highly effective, the literature is sparse regarding the its safety and effectiveness in patients with HIV infection. We will review the risks and benefits of YF immunisation in HIV-infected individuals and consider its use in preventing incident infection in patients infected with HIV.

Description of the condition

Yellow fever is an acute flavivirus infection primarily transmitted by mosquitoes. In jungles and forests in Africa, it is transmitted by Aedes africanus; in South America, it is transmitted by Haemagogus andSabethes species, with New World primates as the primary hosts (WHO 2013b).

Although jaundice is sometimes observed as a symptom of yellow fever, it is often difficult to diagnosis as its clinical presentation is similar to viral hepatitis, malaria, leptospirosis, typhus, and other haemorrhagic fevers (WHO 2013b).

Yellow fever

YF is an acute flavivirus infection primarily transmitted by mosquitoes. In jungles and forests in Africa, it is transmitted by Aedes africanus; in Latin America, it is transmitted by Haemagogus andSabethes species, with New World primates as the primary hosts (WHO 2013b).

Although jaundice is sometimes observed as a symptom of YF, it is often difficult to diagnosis as its clinical presentation is similar to viral hepatitis, malaria, leptospirosis, typhus and other haemorrhagic fevers (WHO 2013b).

There are no known effective medications for YF.

YF vaccine

17D vaccines (17DD and 17D-204) are highly immunogenic and provide an estimated 40 years of protection. More than 600 million YF immunisations have been given worldwide. WHO recommends immunisation for all individuals from > 9 months to 59 years of age, but discourages immunisation for individuals ≥60 years and older as a precaution against risk of severe adverse events.

Reports of severe adverse events caused by YF vaccine are rare. However, neurologic conditions such as encephalitis, myelitis, encephalomyelitis and viscerotropic conditions, such as multiorgan failure of the liver, kidneys and heart, have been reported (WHO 2013b). Since the initial cases of multiorgan failure were published in 2001, more than 50 confirmed and suspected cases of YF vaccine viscerotropic disease (YEL-AVD) have been reported throughout the world (CDC 2010).

Description of the intervention

YF vaccine given to individuals infected with HIV.

How the intervention might work

The intervention may work by stimulating humoral immunity to yellow fever.

Why it is important to do this review

In light of the fact that YF is endemic in tropical Africa and Latin America where large populations of HIV-infected individuals reside, identifying effective YF prevention strategies for people infected with HIV is critical to help prevent disease. Although the U.S. ACIP has stated that YF vaccine is contraindicated in individuals with HIV infection or AIDS, its recommendations are targeted predominantly at travellers from non-endemic areas to endemic areas, who have the option of not going. For HIV-infected patients residing in endemic areas in whom exposure is inevitable, it is important to weigh the risks of vaccination against the risk of developing YF.


To assess the risk and benefits of yellow fever vaccination for people infected with HIV.


Criteria for considering studies for this review

Types of studies

Inclusion criteria

  • Randomised controlled trials, observational studies with comparator or cohort studies

  • Compares HIV-infected and uninfected individuals who received YF vaccine

  • Compares baseline characteristics among proportion of HIV-infected patients who failed to develop nonprotective versus protective titres of YF neutralising antibodies developed in HIV-infected individuals as a result of YF vaccination to those who did develop protective levels of neutralising antibody

Exclusion criteria

  • Case reports and case series without comparison groups

Types of participants

  • HIV-infected individuals (males and females) between 9 months and 60 years old

Types of interventions

  • YF immunisation


  • HIV-uninfected patients

  • HIV-infected patients with different baseline predictor variables

Types of outcome measures

Primary outcomes
  • YF

  • YF neutralising antibody titres (NT) ≥1:10

  • YF vaccine-associated viscerotropic disease (YEL-AVD)

    • Multiorgan failure of the liver, kidneys, heart, and circulation

  • YF vaccine-associated neurologic disease (YEL-AND)

    • Encephalitis

    • Myelitis

    • Encephalomyelitis

Secondary outcomes
  • Mortality

Search methods for identification of studies

See search methods used in reviews by the Cochrane Collaborative Review Group on HIV Infections and AIDS.

Electronic searches

We will formulate a comprehensive search strategy to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress). Full details of the Cochrane HIV/AIDS Review Group methods are published in the section on Collaborative Review Groups in The Cochrane Library.

Journal Databases

We will search the following electronic databases starting in 1981, when the first cases of AIDS were described, through the search date:

  • CENTRAL (Cochrane Central Register of Controlled Trials)


  • PubMed

  • Web of Science

  • World Health Organization (WHO) Global Health Library (, which includes references from AIM (AFRO), LILACS (AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), and WPRIM (WPRO)

Searching other resources

Conference abstract databases

We will search the Aegis archive of HIV/AIDS conference abstracts, which includes abstracts for the following conferences up to 2008:

  • Conferences on Retroviruses and Opportunistic Infections (CROI)

  • International AIDS Society, International AIDS Conferences (IAC)

  • International AIDS Society, Conferences on HIV Pathogenesis, Treatment and Prevention (IAS)

We will searched the conference web sites for abstracts from 2008 to the year of the most recent conference. Additionally, we will examine the references of published articles found in the above databases to identify additional studies.

Data collection and analysis

The methodology for data collection and analysis will be based on the guidance of Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008).

Selection of studies

One author will perform a broad first cut of all downloaded material from the electronic searches to exclude citations that are plainly irrelevant. Two authors will read the titles, abstracts and descriptor terms of the remaining downloaded citations to identify potentially eligible reports. Full text articles will be obtained for all citations identified as potentially eligible and two authors independently will inspect these to establish the relevance of the article according to the pre-specified criteria. If there is uncertainty about the eligibility of the record, the full article will be obtained.

Two authors will independently apply the inclusion criteria, and any differences will be resolved by discussion with a neutral arbiter. Studies will be reviewed for relevance based on study design, types of participants, and outcome measures.

Data extraction and management

Two authors will independently extract data into a standardized, pre-piloted data extraction form. The following characteristics will be extracted from each included study:

  • Administrative details: trial identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year(s) in which study was conducted; details of other relevant papers cited

  • Details of the study: study design; type, duration and completeness of follow-up; location/orientation of study (e.g. higher-income vs. low or middle-income country; stage of HIV epidemic)

  • Details of participants: age range; sex, or sexual orientation if appropriate; clinical characteristics if appropriate, risk for HIV infection, risk for yellow fever

  • Details of intervention: venue; stage of HIV infection when given yellow fever vaccination

  • Details of outcomes

  • Details necessary for risk of bias assessment

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the bias assessment tool described in the Cochrane Handbook (Higgins 2008). We will resolve any disagreement by discussion or by involving a neutral third party.

The Cochrane approach assesses risk of bias in individual studies across six domains: allocation concealment, blinding, incomplete outcome data, selective reporting, sequence generation, and other forms of potential bias.

Allocation concealment (checking for selection bias)

  • Adequate: participants and the investigators enrolling participants cannot foresee assignment

  • Inadequate: participants and investigators enrolling participants can foresee upcoming assignment (e.g., an open random allocation schedule, a list of random numbers), or envelopes were unsealed, non-opaque or not sequentially numbered

  • Unclear: insufficient information to permit judgment of the allocation concealment or the method not described.

Blinding (checking for performance bias and detection bias)

  • Adequate: blinding of the participants, key study personnel and outcome assessor and unlikely that the blinding could have been broken. Not blinding in the situation where non-blinding is unlikely to introduce bias.

  • Inadequate: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

  • Adequate: no missing outcome data, reason for missing outcome data unlikely to be related to true outcome or missing outcome data balanced in number across groups.

  • Inadequate: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.

  • Unclear: insufficient reporting of attrition or exclusions.

Selective reporting

  • Adequate: a protocol is available which clearly states the primary outcome is the same as in the final trial report.

  • Inadequate: the primary outcome differs between the protocol and final trial report.

  • Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Sequence generation (checking for selection bias)

  • Adequate: investigators described a random component in the sequence generation process, such as the use of random number table, coin tossing, card or envelope shuffling.

  • Inadequate: investigators described a non-random component in the sequence generation process, such as the use of odd or even date of birth, algorithm based on the day or date of birth, hospital or clinic record number.

  • Unclear: insufficient information to permit judgment of the sequence generation process

Other forms of bias

  • Adequate: there is no evidence of bias from other sources.

  • Inadequate: there is potential bias present from other sources (e.g., early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).

  • Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias.

For blinding and incomplete outcome data, multiple entries were made if more than one outcome (or time points) is involved.

We will use the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies (Newcastle-Ottawa) to assess the quality and risk of bias in non-randomised studies. Specifically, the scale uses a star system to judge three general areas: selection of study groups, comparability of groups and ascertainment of outcomes (in the case of cohort studies). As a result, this instrument can assess the quality of non-randomised studies so that they can be used in a systematic review.

We will assess the quality of evidence with the GRADE approach (Guyatt 2008), defining evidence quality for each outcome as “the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest” (Higgins 2008). When data for the same outcome from two or more studies can be pooled, evidence quality for that outcome is assessed across the studies providing those data. The quality rating has four levels: high, moderate, low and very low. Data from RCTs are initially considered to provide high quality evidence, but this evidence can be downgraded. Data from non-randomised studies are initially considered to provide low quality evidence, but this evidence can be upgraded or further downgraded. Factors that can decrease evidence quality include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results typically due to small numbers of events or high probability of publication bias. Factors that can increase evidence quality include a large magnitude of effect, all plausible confounding leading to an underestimation of effect, or a dose-response gradient.

Measures of treatment effect

We will use Review Manager 5.1 (RevMan 2011) provided by the Cochrane Collaboration to prepare the review and for statistical analysis. We will summarise dichotomous outcomes for effect using risk ratios (RR), with 95% confidence intervals (CI). If possible, we will calculate summary statistics using meta-analytic methods and present findings in regard to evidence quality in GRADE summary of findings tables, for all outcomes of interest.

Unit of analysis issues

The unit of analysis will be the individual participant.

Dealing with missing data

Study authors will be contacted to obtain missing data if necessary.

Assessment of reporting biases

We will minimise the potential for publication bias by using comprehensive search strategies, which include searching scientific literature from a wide range of databases, published or unpublished, written in any language.

Data synthesis

Meta-analysis will be conducted if appropriate. If meta-analysis is not possible, a narrative synthesis of studies will be undertaken. Data will also be presented using the GRADEpro software (GRADEpro 2011). GRADE evidence profiles and summary of findings tables will be generated.

Sensitivity analysis

If the data allow, we will examine the contributions of individual studies to overall heterogeneity by removing them one at a time.

What's new

15 January 2014AmendedCaught a few typos.

Contributions of authors

All authors contributed to writing this protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • Global Health Sciences, University of California, San Francisco, USA.

External sources

  • No sources of support supplied