Vaccines for the common cold (Protocol)

Felix ML, Guerra CV, Hinojosa MA, Cabezas CI, Hidalgo R, Samaniego DH, Nicola S

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2011, Issue 4 http://www.thecochranelibrary.com

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . WHATS NEW . . . . . . . . HISTORY . . . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 4 4 8 8 11 11 11 11 12

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Protocol]

Vaccines for the common cold

Maria L Felix1 , Claudia V Guerra2 , Miguel A Hinojosa3 , Clarita I Cabezas3 , Ricardo Hidalgo2 , Diana H Samaniego4 , Susana Nicola5
1 Department of Neonatology, Universidad Tecnolgica Equinoccial, Quito, Ecuador. 2 Facultad de Ciencias de la Salud Eugenio Espejo,

Universidad Tecnolgica Equinoccial, Quito, Ecuador. 3 Department of Paediatrics, Universidad Tecnolgica Equinoccial, Quito, Ecuador. 4 Department of Research, Universidad Tecnolgica Equinoccial, Quito, Ecuador. 5 Facultad de Medicina Eugenio Espejo, Universidad Tecnolgica Equinoccial, Quito, Ecuador Contact address: Maria L Felix, Department of Neonatology, Universidad Tecnolgica Equinoccial, Av. Mariana de Jess y Occidental, Quito, Pichincha, 593, Ecuador. mlfelix7@yahoo.com. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: Amended to reect a change in scope (see Whats new), published in Issue 4, 2011. Citation: Felix ML, Guerra CV, Hinojosa MA, Cabezas CI, Hidalgo R, Samaniego DH, Nicola S. Vaccines for the common cold. Cochrane Database of Systematic Reviews 2011, Issue 4. Art. No.: CD002190. DOI: 10.1002/14651858.CD002190.pub3. Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the clinical effectiveness and safety of vaccines to prevent the common cold in healthy people.

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

BACKGROUND
frequent illness among humans. Children experience six to eight URTIs per year (Evans 1997; Nelson 2000) and adults experience two to four episodes per year (Evans 1997; Harrison 2008). The common cold has become a signicant economic burden since it causes frequent absences from school and work (Glezen 2000; Hall 2001; Henrickson 1994; Henrickson 2003) and is estimated to cost the United States more than $60 billion each year (Poland 2009). Furthermore, bacterial complications can lead to morbidity and mortality (Thompson 2003; Wat 2004).

Description of the condition

The common cold is a self-limiting acute upper respiratory tract infection (URTI), characterized by rhinorrhea, nasal congestion, sneezing, cough, sore throat, fever and malaise (Heikkinnen 2003) (Table 1). Despite its benign nature, the common cold is the most Table 1. Viral causes of the common cold Virus Rhinoviruses

Estimated annual proportion of cases

References

30% to 50% Arruda 1997; Gwaltney 1985; Heikkinnen 2003; During autumn 80%, once considered to be lim- Lemanske 2005; Mkel 1998; Monto 1993; ited to the upper airway, is now recognized as an Regamey 2008 important cause for lower respiratory infections 7% to 18% in adults with upper respiratory infec- Larson 1980; Lau 2006; Mkel 1998; Nicholson tions 1997 Responsible for 2.1% of hospital admissions for acute respiratory tract infections in all age groups 5% to 15% Heikkinnen 2003

Coronaviruses

Inuenza viruses Respiratory syncytial virus

In low-income countries, 15% to 20% Berman 1991; Falsey 2005; Thompson 2003 In hospital the proportion of children aged between birth and ve months of age with RSV acute LRTI varied between 9% and 87% Reported in children up to at least 5 years of age, on average 39% (range 20% to 62%) were less than six months old On average age 6 to 11 months comprised 24% of cases (range 14% to 38%) Thus, an average of 63% of children were under 1 year of age On average 20% (range 13% to 29%) of the children were between 1 and 2 years of age. RSV accounts for approximately 10,000 deaths annually in the United States in people over the age of 65 years Respiratory syncytial virus in adults 5% infection annually Acute respiratory infections cause 3% to 18% of Berman 1991; Denny 1983; Henrickson 2003 all admissions to pediatric. hospitals, 9% to 30% of these patients depending on the time of year Parainuenza viruses account for 17% of hospitalized illness-associated virus isolation In low-income countries 7% to 10%
2

Parainuenza viruses

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Table 1. Viral causes of the common cold

(Continued)

50% to 74.2% of croup cases are caused by this virus Adenoviruses Low-income countries can be summarized as 2% Berman 1991 to 4% < 5% 10% short epidemic 20% to 30% Esper 2003; Kahn 2003; Nissen 2002; Risnes 2005 Mkel 1998; Monto 1993

Enteroviruses Metapneumovirus Unknown

LRTI: lower respiratory tract infection RSV: respiratory syncytial virus

The etiology of the common cold is diverse (Table 1) (Heikkinnen 2003). Children, the elderly and other age groups with co-morbidities such as prematurity, chronic lung diseases (chronic obstructive pulmonary disease), congenital heart disease and asthma (Edlmayr 2009; Jackson 2008; Krasinski 1985; Peltola 2008) are more prone to infections by viruses that cause the common cold, such as respiratory syncytial virus (RSV), rhinovirus, parainuenza, coronavirus and adenovirus (non-polio). Human rhinovirus (HRV) is responsible for 50% to 80% of common colds and is an important cause of morbidity, reduced productivity and inappropriate use of antibiotics and over-the-counter (OTC) medications. In humans, the coronavirus (HCoV 229E) causes the common cold by infecting the upper respiratory tract. This is mainly encountered in children and re-infection occurs in adults (Eriksson 2006). The most common factors that contribute to the spread of this disease are primarily poor hand hygiene, overcrowding and captive populations (schools and daycare centres) (Harrison 2008).

Description of the intervention

Treatment of the common cold is symptomatic. Studies have shown that simple preventive measures are important and useful, but it might be difcult to put them into practice (Jefferson 2010). Another measure of prevention would be vaccination. The development of vaccines for the common cold has been difcult because of multiple etiology (Poland 2009) and antigenical variability (Bembridge 1998; Hussell 1998). In the case of rhinovirus, there are over 100 different rhinoviral serotypes (Renwick 2009). For this reason, it is difcult to create a vaccine which can give total protection. However, the future looks promising, considering that we have recently improved our knowledge of HRV by sequencing the full genomes of 99 HRV serotypes (Palmemberg 2009). Immune responses are triggered whenever a person is in-

fected with the same virus but different antigenic molecules (Tobin 2008). The most common causes of respiratory diseases are allergens and the rhinovirus. A recombinant vaccine has been reported, produced with rhinovirus-derived VP1, a surface protein which is critically involved in the infection of respiratory cells, and a nonallergenic peptide of the major grass pollen type allergen Ph1 p1 (Edlmayr 2009). Adenovirus is a commonly-recognized pathogen of the upper respiratory tract and has been particularly frequent in captive populations (Binn 2007). Adenovirus serotype 4 (Ad4) and serotype 7 vaccines were used during immunization programs which started in 1971. Unfortunately, their interruption triggered the re-emergence of adenovirus-produced diseases in crowded locations. An example of this reappearance was documented during 1999, in US military training sites, where Ad4 accounted for 98% of all diagnosed cases (Russell 2006). Epidemiological and clinical studies have revealed important changes with regards to clinical adenovirus infection, including alterations in its antigenic presentation, geographical distribution and virulence (Gray 2007). Adenoviral vaccines delivered orally have been used for decades to prevent respiratory illnesses. New studies have concluded that these vaccines are safe and have brought about a good immune response in the studied populations. RSV causes approximately 5% of common colds in adults (Heikkinnen 2003). The vaccine development for RSV has had some problems due to antigenic variability, especially in proteins F and G. Vaccinated patients with the formalin inactivated vaccine displayed X-ray evidence of severe pneumonia and bronchiolitis due to pulmonary Arthus reaction and a process of immunopotentiation. This process was induced by Th-2 memory

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

cells (Bembridge 1998; Hussell 1998) and the presence of maternal antibodies which could interfere with the response (Anderson 1995). In the case that an effective vaccine can be offered, it should be administered to children younger than six months of age, when their immune system is still immature. Vaccines for parainuenza (HPIV3 cp45) are safe and immunogenic in seronegative children between six and 18 months of age (Belshe 2004a). In addition, the vaccine has demonstrated less risk of transmission than others (wt HPIV3), making it possible to develop more randomized trials. Bovine parainuenza virus vaccines are also being developed and they have been well-tolerated, effective and immunogenic in infants (Belshe 2004b).

with over 189 million missed school days (Roxas 2007) and eight to 20 million days of restricted activity (Adams 1999). 3. If randomized controlled trials (RCTs) demonstrate that there is a vaccine providing efcacy and safety in the prevention of the common cold, scientists could further their research in this area.

OBJECTIVES
To assess the clinical effectiveness and safety of vaccines to prevent the common cold in healthy people.

How the intervention might work

Almost all vaccines work by inducing antibodies in the serum which then interfere with microbial invasion of the bloodstream, or in the mucosa, to block adherence of pathogens to epithelial cells (Pichichero 2009). To protect the body, antibodies must be efcient, neutralizing agents or have opsonization and phagocytosis qualities. Correlates of protection after vaccination are sometimes absolute quantities but often are relative. Most infections are prevented at a particular response level but some of them could occur above that level because of a large challenge dose or decient host factors. There may be more than one correlate of protection for a disease and authors refer to them as co-correlates. Either the effector or central memory may co-correlate with protection. Cellmediated immunity may also operate as a correlate or co-correlate of protection against disease, rather than against infection (Plotkin 2008). Some studies suggest that vaccines which mimic natural infection and the structure of pathogens seem to be effective in inducing long-term protective immunity (Kang 2009).

METHODS

Criteria for considering studies for this review

Types of studies We will include RCTs. We will not apply limits with respect to follow-up periods. Types of participants We will include healthy people, aged from six months to 90 years of age. Types of interventions We will include any vaccine to prevent the common cold which protects against respiratory syncytial virus (RSV), rhinovirus, parainuenza or adenovirus (non-polio), irrespective of dose, schedule or administration route versus placebo. We will not include studies looking at the prevention of inuenza A and B because inuenza and the common cold are two different diseases (Jefferson 2008). See Table 2 for details.

Why it is important to do this review

1. Common cold vaccines would reduce the prevalence of this disease in more than 25 million people with URTIs each year (Gonzales 2001). 2. The common cold causes an important economic burden

Table 2. Comparison of common cold and inuenza characteristics Feature Etiological agent Common cold Inuenza References

Site of infection Symptom onset

> 100 viral strains; rhinovirus 3 strains of inuenza virus; in- Gwaltney 2000 most common uenza A, B, C Gwaltney 1967 Heikkinnen 2003 Upper respiratory tract Entire respiratory system Roxas 2007 Thompson 2003 Gradual: 1 to 3 days Sudden: within a few hours

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Table 2. Comparison of common cold and inuenza characteristics Fever, chills

(Continued)

Occasional, low grade (< 101 F) Characteristic, higher (> 101 F), lasting 2 to 4 days Frequent, usually mild Mild, if any Characteristic, more severe Characteristic, often severe and affecting the entire body

Headache General aches, pains

Cough, chest congestion

Mild to moderate, with hacking Common, may become severe cough Common, usually mild Sometimes present

Sore throat Runny, stuffy nose

Very common, accompanied by Sometimes present bouts of sneezing Mild, if any Usual, may be severe and last 2 to 3 weeks Frequent, usually in early stages of illness

Fatigue, weakness

Extreme exhaustion

Never

Season

Year around, peaks in winter Most cases between November months and February No, unless secondary bacterial in- No, unless secondary bacterial infection develops fection develops

Antibiotics helpful

Types of outcome measures

1. Mortality related to the vaccine.

Search methods for identication of studies

Primary outcomes

1. Incidence of the common cold after vaccination, regardless of the causal agent determined by laboratory or clinical examination. 2. Vaccine safety, i.e. adverse events (any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment (Nebeker 2004)); and adverse drug reactions (a response to a drug which is noxious, uninitiated and which occurs at doses normally used in men for prophylaxis, diagnosis, or therapy of disease, or for the modication of physiologic functions (Nebeker 2004)).

Electronic searches We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), which contains the Cochrane Acute Respiratory Infections Groups Specialized Register, MEDLINE (1950 to present), EMBASE (1974 to present) and LILACS (BIREME) (1982 to present). We will use the following search strategy to search MEDLINE and CENTRAL. We will combine the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision) Ovid format (Lefebvre 2009). We will adapt the search strategy to search the other databases. We will not include any language or publication restrictions.

Secondary outcomes

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

MEDLINE (Ovid)

Data extraction and management Two review authors (CC, DS) will independently extract data from the selected trials using a standardized data extraction form (Zavala 2006). Assessment of risk of bias in included studies Two review authors (RH, MH) will independently assess the quality of each trial using a simple form and will follow the domainbased evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We will compare the assessments and discuss any discrepancies between the review authors. We will resolve any disagreements through discussion. We will assess the following domains as Yes (i.e. low risk of bias), Unclear (uncertain risk of bias) or No (i.e. high risk of bias). 1. Randomization. 2. Allocation concealment. 3. Blinding of participants, personnel and outcome assessors. 4. Incomplete outcome data. 5. Selective outcome reporting. 6. Free of other bias (baseline imbalance, early stopping, academic, drug company involvement) (Gurusamy 2009; Ioannidis 2008a; Ioannidis 2008b). We will use the following denitions.
Generation of the allocation sequence

1 Common Cold/ 2 common cold*.tw. 3 Rhinovirus/ 4 rhinovir*.tw. 5 exp Paramyxoviridae Infections/ 6 parainuenza*.tw. 7 coronavirus/ or coronavirus 229e, human/ or coronavirus oc43, human/ 8 coronavir*.tw. 9 exp adenoviridae/ or adenoviruses, human/ 10 adenovir*.tw. 11 respiratory syncytial viruses/ or respiratory syncytial virus, human/ 12 (respiratory syncytial virus* or rsv).tw. 13 hrv.tw. 14 or/1-13 15 vaccines/ or vaccines, attenuated/ or exp vaccines, combined/ or exp vaccines, inactivated/ or exp vaccines, subunit/ or exp vaccines, synthetic/ or viral vaccines/ or parainuenza vaccines/ or respiratory syncytial virus vaccines/ 16 (vaccin* or innocul* or immuni*).tw. 17 15 or 16 18 14 and 17

Searching other resources We will not impose any language or publication restrictions. We will check the reference lists of all relevant trials and identied reviews. We will search the following websites for trials: 1. Food and Drug Administration (http://www.fda.gov); 2. European Medicines Agency (http://www.emea.europa.eu); 3. Medicines and Healthcare Products Regulatory Agency ( http://www.mhra.gov.uk/index.htm); 4. Scirus (www.scirus.com); 5. Evidence in Health and Social Care (http:// www.evidence.nhs.uk/); and 6. The Clinical Trials Search Portal of the World Health Organization (http://apps.who.int/trialsearch/).

1. Yes (low risk of bias): if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shufing of cards or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure. 2. Unclear (uncertain risk of bias): if the trial was described as randomized, but the method used for the allocation sequence generation was not described. 3. No (high risk of bias): if a system involving dates, names or admittance numbers was used for the allocation of patients. These studies are known as quasi-randomized and will be excluded from the review when assessing benecial effects.
Allocation concealment

Data collection and analysis

Selection of studies Three review authors (MF, CG, SN) will independently assess each reference identied by the searches to decide if they meet the inclusion criteria. We will resolve any disagreements through discussion.

1. Adequate: if the allocation of patients involved a central independent unit, on-site locked computer, identically numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes. 2. Unclear: if the trial was described as randomized, but the method used to conceal the allocation was not described. 3. Inadequate: if the allocation sequence was known to the investigators who assigned participants, or if the study was quasirandomized. The latter will be excluded from the present review when assessing benecial effects.
6

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Blinding (or masking)

We will assess each trial as Yes (i.e. low risk of bias), Unclear (uncertain risk of bias) or No (i.e. high risk of bias) with regard to the following levels of blinding: 1. blinding of clinician (person delivering treatment) to treatment allocation; 2. blinding of participant to treatment allocation; and 3. blinding of outcome assessor to treatment allocation.

reported fully, or it is unclear whether data on these outcomes were recorded or not. 3. No (inadequate): one or more clinically relevant and reasonably expected outcomes were not reported on; although data on these outcomes was likely to have been measured.

Free of other bias (baseline imbalance, early stopping, academic, drug company involvement)

Incomplete outcome data

1. Yes, adequate: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specied that there were no dropouts or withdrawals. 2. Unclear: the report gave the impression that there had been no dropouts or withdrawals, but this was not specically stated. 3. No, inadequate: the number or reasons for dropouts and withdrawals were not described. We will further examine the percentages of dropouts overall in each trial and per randomization arm and we will evaluate whether intention-to-treat (ITT) analysis has been performed or could be performed from the published information.

Were all randomized participants analyzed in the group to which they were allocated? (ITT analysis)

1. Yes (low risk of bias): specically reported by authors that ITT analysis was undertaken and this was conrmed on study assessment, or not stated but evident from study assessment that all randomized participants are reported or analyzed in the group they were allocated to for the most important time point of outcome measurement (minus missing values) irrespective of non-compliance and co-interventions. 2. No (high risk of bias): lack of ITT analysis conrmed on study assessment (patients who were randomized were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation) regardless of whether ITT analysis reported or not. 3. Unclear (uncertain risk of bias): described as ITT analysis, but unable to conrm by study assessment, or not reported and unable to conrm by study assessment. As-treated analysis done with substantial departure from the intervention received from that assigned at randomization; potentially inappropriate application of simple imputation.

1. Yes (low risk of bias); the trial appears to be free of other components that could put it at risk of bias. 2. Unclear (uncertain risk of bias); the trial may or may not be free of other components that could put it at risk of bias. 3. No (high risk of bias); there are other factors in the trial that could put it at risk of bias, for example, no sample size calculation made, early stopping, industry involvement or an extreme baseline imbalance. We will consider trials that achieve a yes for generation of allocation sequence, adequate allocation concealment, adequate blinding, adequate handling of incomplete outcome data, no selective outcome reporting, and are without other bias risks as low risk of bias. Trials at moderate risk of bias will be between the low risk and high risk trials. Trials at high risk of bias are either No or Unclear on the majority of domains. One review author (DS) will enter the data into RevMan (RevMan 2008) and another review author (MH) will check data.

Measures of treatment effect For binary outcomes, we plan to calculate the risk ratio (RR) with 95% condence intervals (CI) for each outcome. 1. Incidence of the common cold. 2. Mortality related to the vaccine.

Unit of analysis issues The unit of analysis will be the included RCTs of the studied participants.

Dealing with missing data We will assess the percentages of dropouts overall for each included trial and for each randomization arm. We will evaluate whether an ITT analysis has been performed or could be performed with the available published information. In order to allow us to undertake an ITT analysis, we will ask the trial authors for data on the number of participants by treatment group (irrespective of compliance) and whether or not the participant was later thought to be ineligible, or otherwise excluded from treatment or follow up.
7

Selective outcome reporting

1. Yes (adequate): pre-dened or clinically relevant and reasonably expected outcomes are reported on. 2. Unclear: not all pre-dened or clinically relevant and reasonably expected outcomes are reported on or are not

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Assessment of heterogeneity We will use the Chi2 test, taking P < 0.1 as signicant. We will explore sources of heterogeneity in the assessment of the primary outcome measure by subgroup analyses. We will also attempt to assess whether the review is subject to publication bias by using a funnel plot to illustrate variability between trials graphically. If asymmetry is detected, we will explore causes other than publication bias. We will conduct a funnel plot analysis if 10 or more RCTs are included. Assessment of reporting biases We will quantify statistical heterogeneity using the I2 statistic, which describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins 2003). We will consider there to be signicant statistical heterogeneity if the I2 statistic is greater than 50% (Higgins 2009). Data synthesis We will carry out statistical analysis using the Review Manager software (RevMan 2008). We will use xed-effect inverse variance meta-analysis for combining data where trials are examining the same intervention and the trials populations and methods are judged sufciently similar. Where we suspect clinical or methodological heterogeneity between studies sufcient to suggest that treatment effects may differ between trials, we will use randomeffects meta-analysis. If substantial heterogeneity is identied in a xed-effect meta-analysis we will note this and repeat the analysis using a random-effects model.

Subgroup analysis and investigation of heterogeneity We anticipate clinical heterogeneity in the effect of the intervention and we propose to conduct the following sub-group analyses: 1. children and adults; 2. country of study; and 3. different responses in relation to different viral agents. We will only perform a subgroup analysis for primary outcomes.

Sensitivity analysis If sufcient trials are identied, we plan to conduct a sensitivity analysis comparing the results of all trials. We will classify studies as having a low risk of bias versus those identied as having a high risk of bias (Higgins 2009). We will also evaluate the risk of attrition bias, as estimated by the percentage of participants lost. We will exclude from the meta-analysis, but include in the review, trials with a total attrition of more than 20% or where differences between the groups exceed 10%, or both.

ACKNOWLEDGEMENTS
Tom Jefferson and David Tyrell co-authored the rst published version of this protocol. The authors wish to thank the following people for commenting on this draft protocol: Anne Lyddiatt, Gulam Khandaker, Lisa Jackson, Mark Grifn and Meenu Singh.

REFERENCES

Additional references
Adams 1999 Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey 1996. Vital Health Statistics 1999;10(200):1203. [MEDLINE: 15782448] Anderson 1995 Anderson L, Heilman C. Protective and disease-enhancing immune responses to respiratory syncytial virus. Journal of Infectious Diseases 1995;171(1):17. [MEDLINE: 7798649] Arruda 1997 Arruda E, Pitkranta A, Witek TJ Jr, Doyle CA, Hayden FG. Frequency and natural history of rhinovirus infections in adults during autumn. Journal of Clinical Microbiology 1997;35(11): 28648. [MEDLINE: 9350748] Belshe 2004a Belshe RB, Newman FK, Anderson EL, Wright PF, Karron RA, Tollefson S. Evaluation of combined live, attenuated respiratory syncytial virus and parainuenza 3 virus vaccines in infants and

young children. Journal of Infectious Diseases 2004;190(12): 2096103. [MEDLINE: 15551207] Belshe 2004b Belshe RB, Newman FK, Tsak TF, Karron RA, Reisinger K, Roberton D. Phase 2 evaluation of parainuenza type 3 cold passage mutant 45 live attenuated vaccine in healthy children 6-18 months old. Journal of Infectious Diseases 2004;189(3):46270. [MEDLINE: 14745704] Bembridge 1998 Bembridge G, Garcia-Beato R, Lpez J, Melero J, Taylor G. Subcellular site of expression and route of vaccination inuence pulmonary eosinophilia following respiratory syncytial virus challenge in BALB/c mice sensitized to the attachment G protein. Journal of Immunology 1998;161(5):247380. [MEDLINE: 9725246] Berman 1991 Berman S. Epidemiology of acute respiratory infections in children of developing countries. Reviews of Infectious Diseases 1991;13 (Suppl 6):45462. [MEDLINE: 1862276]
8

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Binn 2007 Binn LN, Sanchez JL, Gaydos JC. Emergence of adenovirus type 14 in US military recruits - a new challenge. Journal of Infectious Diseases 2007;196(10):14367. [MEDLINE: 18008220] Denny 1983 Denny FW, Murphy TF, Clyde WA, Collier AM, Henderson FW. Croup: an 11 year study in a pediatric practice. Pediatrics 1983;71 (6):8716. [MEDLINE: 6304611] Edlmayr 2009 Edlmayr J, Niespodziana K, Linhart B, Focke-Tejk lM, Westrtschnig K, Scheiblhober S, et al.A combination vaccine for allergy and rhinovirus infections based on rhinovirus-derived surface protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen PHl p1. Journal of Immunology 2009; 182(10):6298306. [MEDLINE: 19414783] Eriksson 2006 Eriksson KK, Makia D, Maier R, Ludewig B, Thiel V. Towards a coronavirus-based HIV multigene vaccine. Clinical & Development Immunology 2006;13(2-4):35360. [MEDLINE: 17162377] Esper 2003 Esper F, Boucher D, Weibel C, Martinello RA, Kahn JS. Human metapneumovirus infection in the United States: clinical manifestations associated with a newly emerging respiratory infection in children. Pediatrics 2003;111(6 pt 1):140710. [MEDLINE: 12777560] Evans 1997 Evans AS, Kaslow RA, editors. Viral Infection of Humans: Epidemiology and Control. 4th Edition. New York: Plenum Press, 1997. Falsey 2005 Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. New England Journal of Medicine 2005;352(17):174959. [MEDLINE: 15858184] Glezen 2000 Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory infection on persons with chronic underlying conditions. JAMA 2000;283(4):499505. [MEDLINE: 10659876] Gonzales 2001 Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clinical Infectious Diseases 2001;33(6):75762. [MEDLINE: 11512079] Gray 2007 Gray GC, McCarthy T, Lebeck MG, Schnurr OP, Russell KL, Kajon AE, et al.Genotype prevalence and risk factors for severe clinical adenovirus infection, United States 2004-2006. Clinical Infectious Diseases 2007;45(9):112031. [MEDLINE: 17918073] Gurusamy 2009 Gurusamy KS, Gluud C, Nikolova D, Davidson BR. Assessment of risk of bias in randomized clinical trials in surgery. British Journal of Surgery 2009;96(4):3429. [MEDLINE: 19283747]

Gwaltney 1967 Gwaltney JM, Hendley J, Simon G, Jordan WSJ. Rhinovirus infections in an industrial population II. Characteristics of illness and antibody response. JAMA 1967;202(6):494500. Gwaltney 1985 Gwaltney JM. Virology and immunology of the common cold. Rhinology 1985;23(4):26571. [MEDLINE: 3001912] Gwaltney 2000 Gwaltney JM. The common cold. In: Mandell GL, Bennett JE, Dolin R editor(s). Principles and Practices of Infectious Diseases. 5th Edition. New York: Churchill Livingstone, 2000:6516. Hall 2001 Hall CV. Respiratory syncytial virus and parainuenza virus. New England Journal of Medicine 2001;344(25):191728. [MEDLINE: 11419430] Harrison 2008 Fauci AS, Brownwald E, Kasper D, Hauser S, Longo D, Hameson L, et al.Harrison Principios de Medicina Interna. 17th Edition. McGraw Hill, 2008. Heikkinnen 2003 Heikkinen T, Jarvinen A. The common cold. Lancet 2003;361 (9351):519. [MEDLINE: 12517470] Henrickson 1994 Henrickson KJ, Kuhn SM, Savatski LL. Epidemiology and cost of infection with human parainuenza viruses types 1 and 2 in young children. Clinical Infectious Diseases 1994;18(5):7709. [MEDLINE: 8075269] Henrickson 2003 Henrickson KJ. Parainuenza viruses. Clinical Microbiology Reviews 2003;16(2):24264. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):55760. [MEDLINE: 12958120] Higgins 2009 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: Wiley-Blackwell, 2009. Hussell 1998 Hussell T, Georgiou A, Sparer T, Matthews S, Pala P, Openshaw P. Host genetic determinants of vaccine-induced eosinophilia during RSV infection. Journal of Immunology 1998;161(11):621522. [PUBMED: 9834108] Ioannidis 2008a Ioannidis JP. Why most discovered true associations are inated. Epidemiology 2008;19(5):6408. [MEDLINE: 18633328] Ioannidis 2008b Ioannidis JP. Perfect study, poor evidence: interpretation of biases preceding study design. Seminars in Hematology 2008;45(3):1606. [MEDLINE: 18582622] Jackson 2008 Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. American Journal of Respiratory and Critical Care Medicine 2008;178(7):66772. [MEDLINE: 18565953]
9

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Jefferson 2008 Jefferson T, Rivetti A, Harnden AR, Di Pietrantonj C, Demicheli V. Vaccines for preventing inuenza in healthy children. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/ 14651858.CD004879.pub3] Jefferson 2010 Jefferson T, Del Mar C, Dooley L, Ferroni E, Al-Ansary LA, Bawazeer GA, et al.Physical interventions to interrupt or reduce the spread of respiratory viruses. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/ 14651858.CD006207.pub3] Kahn 2003 Kahn JS. Human metapneumovirus: a newly emerging respiratory pathogen. Current Opinion in Infection Diseases 2003;16(3):2558. [MEDLINE: 12821817] Kang 2009 Kang SM, Compans RW. Host responses from innate to adaptive immunity after vaccination: molecular and cellular events. Molecular Cell 2009;27(1):514. [MEDLINE: 19214429] Krasinski 1985 Krasinski. Severe respiratory syncytial virus infection: clinical features, nosocomial acquisition and outcome. Pediatric Infectious Disease 1985;4(3):2507. [MEDLINE: 4000987] Larson 1980 Larson HE, Reed SE, Tyrrell DA. Isolation of rhinoviruses and coronaviruses from 38 colds in adults. Journal of Medical Virology 1980;5(3):2219. [MEDLINE: 6262450] Lau 2006 Lau S, Woo P, Yip L, Tse H, Tesoi H, Ching V, et al.Coronavirus HKU1 and other coronavirus infection in Hong Kong. Journal of Clinical Microbiology 2006;44(6):206371. [MEDLINE: 16757599] Lefebvre 2009 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: WileyBlackwell, 2009. Lemanske 2005 Lemanske RF Jr, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. Journal of Allergy and Clinical Immunology 2005;116(3):5717. [MEDLINE: 16159626] Monto 1993 Monto AS, Sullivan KM. Acute respiratory illness in the community. Frequency of illness and the agents involved. Epidemiology and Infection 1993;110(1):14560. [MEDLINE: 8432318] Mkel 1998 Mkel MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimki M, et al.Viruses and bacteria in the etiology of the common cold. Journal of Clinical Microbiology 1998;36(2):53942. [MEDLINE: 9466772] Nebeker 2004 Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinicians guide to terminology, documentation, and reporting.

Annals of Internal Medicine 2004;140(10):795801. [MEDLINE: 15148066] Nelson 2000 Robert M, Kliegman MD, Richard E, Behrman MD, Hal B, et al.Nelson Textbook of Pediatrics. Nelson Tratado de Pediatra. 16th Edition. McGraw Hill, 2000. Nicholson 1997 Nicholson KG, Kent J, Hammersley V, Cancio E. Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective population based study of disease burden. BMJ 1997;315(7115):10604. Nissen 2002 Niessen MD, Siebert DJ, Mackay IM, Sloots TP, Withers SJ. Evidence of human metapneumovirus in Australian children. Medical Journal of Australia 2002;176(4):188. [MEDLINE: 11913922] Palmemberg 2009 Palmemberg AC, Spiro D, Kuzmickas R, Wang S, Djikeng A, Rathe JA, et al.Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution. Science 2009; 324(5923):559. [MEDLINE: 19213880] Peltola 2008 Peltola V, Waris M, Osterback R, Susi P, Hyypi T, Ruuskanen O. Clinical effects of rhinovirus infections. Journal of Clinical Virology 2008;43(4):4114. [MEDLINE: 18835215] Pichichero 2009 Pichichero ME. Booster vaccinations: can immunologic memory outpace disease pathogenesis?. Pediatrics 2009;124(6):163341. [MEDLINE: 19933727] Plotkin 2008 Plotkin SA. Vaccines: correlates of vaccine-induced immunity. Clinical Infectious Diseases 2008;47(3):4019. [MEDLINE: 18558875] Poland 2009 Poland G, Barry MA. Common cold, uncommon variation. New England Journal of Medicine 2009;360(21):22456. [MEDLINE: 19458372] Regamey 2008 Regamey N, Kaiser L. Rhinovirus infections in infants: is respiratory syncytial virus ready for the challenge?. European Respiratory Journal 2008;32(2):24951. [MEDLINE: 18669781] Renwick 2009 Renwick N, Schweiger B, Kapoor B, Liu Z, Villari J, Bullmann R, et al.A recently identied rhinovirus genotype is associated with severe respiratory tract infection in children in Germany. Journal of Infectious Diseases 2007;196(12):175460. RevMan 2008 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Risnes 2005 Risnes KR, Radtke A, Nordb SA, Grammeltvedt AT, Dllner H. Human metapneumovirus - occurrence and clinical signicance. Tidsskrift for den Norske Lgeforening 2005;20:276972. [MEDLINE: 16244677]
10

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Roxas 2007 Roxas M, Jurenka J. Colds and inuenza: a review of diagnosis and conventional, botanical and nutritional considerations. Alternative Medicine Review 2007;12(1):2548. [MEDLINE: 17397266] Russell 2006 Russell KL, Hawksworth AW, Ryan MA, Strickler J, Irvine M, Hansen CJ, et al.Vaccine-preventable adenoviral respiratory illness in US military recruits, 1999-2004. Vaccine 2006;24(15):283542. [MEDLINE: 16480793] Thompson 2003 Thompson WW. Mortality associated with inuenza and respiratory syncytial virus in the United States. JAMA 2003;289(2): 17986. [MEDLINE: 12517228]

Tobin 2008 Tobin G, Trujillo JD, Bushnell R, Lin G, Chaudhuri RA, Largo J, et al.Deceptive imprinting and immune refocusing in vaccine design. Vaccine 2008;26(49):618999. Wat 2004 Wat D. The common cold: a review of the literature. European Journal of Internal Medicine 2004;15(2):7988. [MEDLINE: 15172021] Zavala 2006 Zavala D, Marti A, Pea-Marti G, Comunin G. Sheet to enter data for performing a Cochrane review. http:// www.cochrane.fcs.uc.edu.ve/hrs. Valencia, Venezuela: Universidad de Carabobo, 2006. Indicates the major publication for the study

WHATS NEW

Date 8 September 2009

Event New citation required and major changes

Description Protocol taken over by a new team of review authors.

HISTORY
Protocol rst published: Issue 3, 2000

Date 26 February 2009 4 August 2008

Event Amended Amended

Description Protocol withdrawn Issue 3, 2009. Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Diana Samaniego (DS) and Susana Nicola (SN) provided methodological support. Maria Felix (MF), Clarita Cabezas (CC), Claudia Guerra (CG), Miguel Hinojosa (MH) and Ricardo Hidalgo (RH) wrote the nal protocol.

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

11

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT Internal sources

Universidad Tecnolgica Equinoccial, Ecuador. Methodological

External sources
No sources of support supplied

Vaccines for the common cold (Protocol) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

12