Vaccines for the common cold

  • Review
  • Intervention

Authors


Abstract

Background

The common cold is a spontaneously remitting infection of the upper respiratory tract, characterised by a runny nose, nasal congestion, sneezing, cough, malaise, sore throat and fever (usually < 37.8˚C). The widespread morbidity it causes worldwide is related to its ubiquitousness rather than its severity. The development of vaccines for the common cold has been difficult because of antigenic variability of the common cold virus and the indistinguishable multiple other viruses and even bacteria acting as infective agents. There is uncertainty regarding the efficacy and safety of interventions for preventing the common cold in healthy people.

Objectives

To assess the clinical effectiveness and safety of vaccines for preventing the common cold in healthy people.

Search methods

We searched CENTRAL (2012, Issue 12), MEDLINE (1948 to January week 1, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013) and LILACS (1982 to January 2013).

Selection criteria

Randomised controlled trials (RCTs) of any virus vaccines to prevent the common cold in healthy people.

Data collection and analysis

Two review authors independently evaluated methodological quality and extracted trial data. Disagreements were resolved by discussion or by consulting a third review author.

Main results

This review included one RCT with 2307 healthy participants; all of them were analysed. This trial compared the effect of an adenovirus vaccine against a placebo. No statistically significant difference in common cold incidence was found: there were 13 events in 1139 participants in the vaccines group and 14 events in 1168 participants in the placebo group; risk ratio (RR) 0.95, 95% confidence interval (CI) 0.45 to 2.02, P = 0.90). No adverse events related to the live vaccine were reported.

Authors' conclusions

This Cochrane review has found a lack of evidence on the effects of vaccines for the common cold in healthy people. Only one RCT was found and this did not show differences between comparison groups; it also had a high risk of bias. There are no conclusive data to support the use of vaccines for preventing the common cold in healthy people. We identified the need for well-designed, adequately powered RCTs to investigate vaccines for the common cold in healthy people. Unless RCTs provide evidence of a treatment effect and the trade-off between potential benefits and harms is established, policy-makers, clinicians and academics should not recommend the use of vaccines for preventing the common cold in healthy people. Any future trials on medical treatments for preventing the common cold should assess a variety of virus vaccines for this condition. Outcome measures should include common cold incidence, vaccine safety and mortality related to the vaccine.

Résumé scientifique

Les vaccins contre le rhume

Contexte

Le rhume est une infection spontanément rémittente des voies respiratoires supérieures, qui se caractérise par des écoulements, une congestion nasale, des éternuements, la présence de toux, des malaises, des maux de gorge et de la fièvre (généralement < 37,8°C). La morbidité étendue qu'il cause à travers le monde est liée à son ubiquité plutôt qu'à sa gravité. Le développement des vaccins contre le rhume courant a été difficile en raison de la variabilité antigène du virus du rhume et des multiples autres virus indétectables, voire des bactéries agissant comme agents infectieux. Il subsiste des doutes quant à l'efficacité et l'innocuité des interventions pour prévenir le rhume chez les personnes en bonne santé.

Objectifs

Evaluer l'efficacité clinique et l'innocuité des vaccins utilisés pour prévenir le rhume chez les personnes en bonne santé.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (2012, Numéro 12), MEDLINE (de 1948 à la 1ère semaine de janvier 2013), EMBASE (de 1974 à janvier 2013), CINAHL (de 1981 à janvier 2013) et LILACS (de 1982 à janvier 2013).

Critères de sélection

Les essais contrôlés randomisés (ECR) portant sur des vaccins viraux pour prévenir le rhume chez les personnes en bonne santé.

Recueil et analyse des données

Deux auteurs de la revue ont évalué la qualité méthodologique des essais et en ont extrait les données, de manière indépendante. Les désaccords ont été résolus par la discussion ou en consultation avec un troisième auteur.

Résultats principaux

Cette revue incluait un ECR avec 2307 participants en bonne santé ; ils ont tous été analysés. Cet essai comparait l'effet d'un vaccin adénovirus par rapport à un placebo. Aucune différence statistiquement significative dans l'incidence du rhume n'a été trouvée : il a été constaté 13 évènements chez 1139 participants du groupe avec vaccins et 14 évènements chez 1168 participants du groupe avec placebo ; rapport de risque (RR) 0,95, intervalle de confiance (IC) à 95 % 0,45 à 2,02, P = 0,90). Aucun effet indésirable lié au vaccin vivant n'a été signalé.

Conclusions des auteurs

Cette revue Cochrane a démontré qu'il n'y avait pas suffisamment de données sur l'effet des vaccins contre le rhume chez les personnes en bonne santé. Seul un ECR a été trouvé, il ne mentionnait aucune différence entre les groupes de comparaison ; il avait également un risque de biais élevé. Il n'y a pas de données concluantes permettant de soutenir l'utilisation des vaccins pour prévenir le rhume chez les personnes en bonne santé. Nous avons identifié le besoin de réaliser des ECR bien conçus et suffisamment puissants pour enquêter sur les vaccins contre le rhume chez les personnes en bonne santé. A moins que les ECR fournissent des données sur l'effet d'un traitement et que l'arbitrage entre les bénéfices et les inconvénients potentiels soit établi, les décisionnaires, les cliniciens et les universitaires ne devraient pas recommander l'utilisation des vaccins pour prévenir le rhume chez les personnes en bonne santé. Tout essai ultérieur sur les traitements médicaux pour prévenir le rhume devrait évaluer une multitude de vaccins viraux pour cette affection. Les mesures de résultats devraient inclure l'incidence du rhume, l'innocuité du vaccin et la mortalité liée au vaccin.

Plain language summary

Vaccines for preventing the common cold in healthy people

The common cold is a self limiting viral infection of the upper respiratory tract, characterised by a runny nose, nasal congestion, sneezing, cough, malaise, with or without sore throat, and a slightly elevated temperature. Treatment is symptomatic. Vaccines for preventing the common cold have been difficult to produce because the sources and antigens of the virus vary greatly. Globally, the common cold causes widespread morbidity. The efficacy and safety of interventions for preventing the common cold in healthy people are still uncertain.

This Cochrane review identified only one randomised controlled trial (RCT) involving 2307 healthy people. The trial compared adenovirus vaccines with a placebo to prevent the common cold in healthy people. No statistically significant difference in common cold incidence was found. This RCT report no adverse events related to the live vaccine. The trial had a high risk of bias. The existing evidence does not support adenovirus vaccines to prevent the common cold in healthy people. How far virus vaccines can reduce the incidence of the common cold still remains to be investigated.

Résumé simplifié

Les vaccins pour la prévention du rhume chez les personnes en bonne santé

Le rhume est une infection virale des voies aériennes supérieures qui se résorbe d'elle même, caractérisée par des écoulements, une congestion nasale, des éternuements, la présence de toux, des malaises, avec ou sans maux de gorge, et une légère fièvre. Le traitement est symptomatique. Les vaccins pour prévenir le rhume sont difficiles à produire parce que les sources et les antigènes du virus varient énormément. Globalement, le rhume entraîne une morbidité étendue. L'efficacité et l'innocuité des interventions pour prévenir le rhume chez les personnes en bonne santé restent incertaines.

Cette revue Cochrane a identifié un seul essai contrôlé randomisé (ECR) totalisant 2307 personnes en bonne santé. L'essai comparait les vaccins adénovirus à un placebo pour prévenir le rhume chez les personnes en bonne santé. Aucune différence statistiquement significative dans l'incidence du rhume n'a été trouvée. Cet ECR ne mentionnait aucun effet indésirable lié au vaccin vivant. L'essai présentait un risque de biais élevé. Les données existantes ne soutiennent pas les vaccins adénovirus pour prévenir l'apparition du rhume chez les personnes en bonne santé. Il est nécessaires de réaliser d'autres recherches pour savoir si les vaccins viraux peuvent diminuer l'incidence du rhume.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. Virus vaccines compared to placebo for preventing the common cold in healthy people
  1. 1Adenovirus vaccine used for preventing the common cold.
    2 Griffin 1970.
    3Almost all assessed methodological quality domains are at unclear risk or high risk.
    4Few events (N = 27).
    595% confidence interval is wide.

Virus vaccines compared to placebo for preventing the common cold in healthy people
Patient or population: healthy people
Settings: outpatients at Great Lakes Naval Training Center
Intervention: virus vaccines for preventing the common cold1
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Virus vaccines for preventing the common cold
Incidence of the common cold
Number of participants with common cold by group
Follow-up: mean 9 weeks
Study population RR 0.95
(0.45 to 2.02)
2307
(1 study)2
⊕⊕⊝⊝
low 3,4,5
 
12 per 1000 11 per 1000
(5 to 24)
Moderate
  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

 

Description of the condition

There are no standardised definitions for a common cold. The common cold is a spontaneously remitting infection of the upper respiratory tract, characterised by a runny nose, nasal congestion and sneezing, and sometimes cough, malaise, sore throat and fever (usually < 100˚F). A temperature of 100°F (37.8ºC) or higher for three to four days is typically associated with influenza and other respiratory diseases (DDCP 2010; Heikkinen 2003) (Appendix 1). Despite its benign nature, the common cold is the most frequent illness experienced in humans. Children experience six to eight upper respiratory tract infections (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 significant 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 USD 60 billion each year (Poland 2009). Furthermore, bacterial complications can lead to morbidity and mortality (Thompson 2003; Wat 2004). 

The aetiology of the common cold is diverse (Appendix 2) (Heikkinen 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, parainfluenza, 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 but may be difficult to enforce practically (Jefferson 2011). Another method of prevention would be vaccination. 

The development of vaccines for the common cold has been difficult because of multiple aetiologies (Poland 2009) and antigenic variability of the common cold viruses (Bembridge 1998; Hussell 1998). In the case of rhinovirus, there are over 100 different rhinoviral serotypes (Renwick 2009). For this reason, it is difficult 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 infected with the same virus but with different antigenic molecules (Tobin 2008). 

One of the most common causes of respiratory diseases are rhinoviruses. 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 non-allergenic peptide of the major grass pollen type allergen Ph1 p1 (Edlmayr 2009).

Adenovirus is a commonly recognised pathogen of the upper respiratory tract and has been particularly common in captive populations (Binn 2007). Adenovirus serotype 4 (Ad4) and serotype 7 vaccines were used during immunisation programmes 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 (Heikkinen 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 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 parainfluenza (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 randomised trials. Bovine parainfluenza virus vaccines are also being developed and they have been well-tolerated, effective and immunogenic in infants (Belshe 2004b).  

How the intervention might work

Almost all vaccines work by inducing antibodies in the serum to interfere with microbial invasion of the bloodstream, or in the mucosa and to block adherence of pathogens to epithelial cells (Pichichero 2009). To protect the body, antibodies must be efficient, neutralising agents or have opsonisation 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 deficient 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. Cell-mediated 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 take into account the structure of pathogens seem to be effective in inducing long-term protective immunity (Kang 2009).  

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 with over 189 million missed school days (Roxas 2007) and eight to 20 million days of restricted activity (Adams 1999). 

  3. If randomised controlled trials (RCTs) demonstrate that there is a vaccine providing efficacy and safety in the prevention of the common cold, scientists could continue their research in this area.

Objectives

To assess the clinical effectiveness and safety of vaccines for preventing the common cold in healthy people.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). We did not apply limits with respect to follow-up periods.

Types of participants

Healthy people between six months to 90 years of age.

Types of interventions

Any vaccine that prevents the common cold, which protects against respiratory syncytial virus (RSV), rhinovirus, parainfluenza or adenovirus (non-polio), irrespective of dose, schedule or administration route, versus placebo. We excluded trials looking at the prevention of influenza A and B because influenza and the common cold are two different diseases (Jefferson 2012). See Appendix 2 for details.

Types of outcome measures

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 modification of physiologic functions" (Nebeker 2004)).

  3. Mortality related to the vaccine.

Search methods for identification of studies

Electronic searches

We searched CENTRAL (2012, Issue 12), part of The Cochrane Library, www.thecochranelibrary.com (accessed 12 January 2012), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1948 to January week 1, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013) and LILACS (1982 to January 2013).

We used the following search strategy to search MEDLINE and CENTRAL. We combined the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision), Ovid format (Lefebvre 2011). We adapted the search strategy to search EMBASE (see Appendix 3), CINAHL (see Appendix 4) and LILACS (see Appendix 5). We did not include any language or publication restrictions.

MEDLINE (Ovid)

1 Common Cold/
2 common cold*.tw.
3 coryza.tw.
4 (acute adj5 (upper respiratory infection* or upper respiratory tract infection* or urti or uri)).tw.
5 Picornaviridae Infections/
6 Rhinovirus/
7 rhinovir*.tw.
8 hrv.tw.
9 Paramyxoviridae Infections/
10 parainfluenza virus 1, human/ or parainfluenza virus 3, human/
11 parainfluenza virus 2, human/ or parainfluenza virus 4, human/
12 parainfluenza*.tw.
13 coronavirus/ or coronavirus 229e, human/ or coronavirus oc43, human/
14 Coronavirus Infections/
15 coronavir*.tw.
16 exp adenoviridae/ or adenoviruses, human/
17 Adenovirus Infections, Human/
18 adenovir*.tw.
19 respiratory syncytial viruses/ or respiratory syncytial virus, human/
20 Respiratory Syncytial Virus Infections/
21 (respiratory syncytial virus* or rsv).tw.
22 or/1-21
23 exp Vaccines/
24 exp Vaccination/
25 (vaccin* or inocul* or immuni*).tw.
26 or/23-25
27 22 and 26

Searching other resources

We checked the reference lists of all relevant trials and identified reviews. We searched 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/).

Data collection and analysis

Selection of studies

Two review authors (DSR, VG) independently assessed for inclusion all the potential studies which were identified as a result of the search strategy. We resolved any disagreement through discussion and we consulted with a third review author (RHO).

Data extraction and management

Two review authors (DSR, CVG) independently extracted data from the selected trials using a standardised data extraction form (Zavala 2006). We consulted a third review author (RHO) in the event of any disagreements, which we resolved through discussion and consensus. We extracted the following data: eligibility criteria, demographics (age, gender, country), follow-up (weeks), type of vaccines, setting of the patients and outcomes.

Assessment of risk of bias in included studies

Three review authors (DSR, CVG, RHO) independently assessed the quality of each trial using a simple form following the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We compared the assessments and discussed any discrepancies between the review authors. We resolved disagreements through discussion and consensus. This section was checked by a review author (RHO).

We assessed the following domains as low, unclear or high risk of bias.

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding (of participants, personnel and outcome assessors).

  4. Incomplete outcome data.

  5. Selective reporting.

  6. Other bias (baseline imbalance, early stopping, drug company involvement) (Gurusamy 2009; Ioannidis 2008a; Ioannidis 2008b).

We used the following definitions as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Generation of the allocation sequence
  • Low risk, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards or throwing dice was considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.

  • Unclear risk, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.

  • High risk, if a system involving dates, names or admittance numbers was used for the allocation of patients.

Allocation concealment
  • Low risk, if the allocation of patients involved a central independent unit, on-site locked computer, identically appearing, numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes.

  • Unclear risk, if the trial was described as randomised, but the method used to conceal the allocation was not described.

  • High risk, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi-randomised.

Blinding (or masking)

We assessed each trial (as low, unclear or high risk) with regard to the following types of blinding:

  • blinding of clinician (person delivering treatment) to treatment allocation;

  • blinding of participant to treatment allocation;

  • blinding of outcome assessor to treatment allocation.

Incomplete outcome data
  • Low risk, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.

  • Unclear risk, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.

  • High risk, if the number or reasons for dropouts and withdrawals were not described.

We further examined the percentages of dropouts overall in each trial and per randomisation arm and we evaluated whether intention-to-treat (ITT) analysis was performed or could be performed from the published information.

Selective outcome reporting
  • Low risk, if pre-defined or clinically relevant and reasonably expected outcomes were reported on.

  • Unclear risk, if not all pre-defined or clinically relevant and reasonably expected outcomes were reported on or were not reported on fully, or it was unclear whether data on these outcomes were recorded or not.

  • High risk, if one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.

Other bias (baseline imbalance, early stopping, drug company involvement)
  • Low risk, if the trial appears to be free of other components that could put it at risk of bias.

  • Unclear risk, if the trial may or may not be free of other components that could put it at risk of bias.

  • High risk, if there are other factors in the trial that could put it at risk of bias, e.g. early stopping, industry involvement or an extreme baseline imbalance.

We considered low risk of bias trials to be those that adequately generated their allocation sequence; had adequate allocation concealment, blinding and handling of incomplete outcome data; were free of selective outcome reporting; and were free of other bias.

We considered trials in which we assessed at least one of the domains as having a high risk of bias, or unclear risk of bias, to be trials with high risk of bias.

Measures of treatment effect

We calculated the risk ratio (RR) with 95% confidence intervals (CIs) for the following binary outcome: incidence of the common cold.

Unit of analysis issues

The unit of analysis was the studied participants. We collected and analysed a single measurement for each outcome from each participant.

Dealing with missing data

Levels of attrition were not noted for the included study (Griffin 1970). For future updates of this review, we will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. Also, we will carry out the ITT analysis by using the imputation method (worse-case scenario versus best-case scenario).

Assessment of heterogeneity

This review does not include a meta-analysis. For future updates, we will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity (I² statistic > 50%) we will explore it by a pre-specified subgroup analysis (Higgins 2011).

Assessment of reporting biases

We did not assess publication bias using a funnel plot because we included only one trial. For future updates, we will attempt to assess whether the review is subject to publication bias by using a funnel plot if ≥ 10 trials are included.

Data synthesis

We carried out statistical analysis using Review Manager software (RevMan 2012). For future updates, we will summarise findings using a fixed-effect model according the Cochrane Handbook of Systematic Reviews for Interventions (Higgins 2011).

'Summary of findings'

We used the principles of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to assess the quality of the body of evidence associated with specific outcomes (incidence of the common cold) in our review (Balshem 2011; Brozek 2011; Guyatt 2008; Guyatt 2011h). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality of a body of evidence takes into consideration within-study risk of bias (methodological quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias (Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g).

For future updates, we will also assess the quality of the body of evidence associated with specific outcomes (incidence of the common cold, vaccine safety, mortality related to vaccine administration).

Subgroup analysis and investigation of heterogeneity

In subsequent updates of this review, when sufficient data are available, we plan to carry out the following subgroup analyses:

  1. children and adults;

  2. country of study; and

  3. different responses in relation to different viral agents.

We will explore sources of heterogeneity in the assessment of the primary outcome measure by subgroup analyses and meta-regression analyses. The meta-regression analyses will assess the effect of methodological quality (high versus low), type of virus vaccines and patients' characteristics. We will only conduct meta-regression if ≥ 10 RCTs are included.

Sensitivity analysis

For future updates, we plan to conduct a sensitivity analysis comparing the results using all trials as follows.

  1. Those trials with high methodological quality (studies classified as having a 'low risk of bias' versus those identified as having a 'high risk of bias') (Higgins 2011).

  2. Those trials that performed intention-to treat versus per-protocol analyses.

We will also evaluate the risk of attrition bias, as estimated by the percentage of participants lost. Trials with a total attrition of more than 30%, or where differences between the groups exceed 10%, or both, will be excluded from meta-analysis but will be included in the review.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies tables.

Results of the search

We retrieved and analysed 841 results from our electronic searches run in January 2013. See Figure 1. A total of 334 records were duplicates. We excluded 799 records based on title and abstract. We assessed 42 full-text articles for eligibility and excluded 41 of them. We excluded 22 trials because they did not evaluate the common cold as an outcome. Only one study (Griffin 1970) was included.

Figure 1.

Study flow diagram

Included studies

This review identified one randomised controlled trial (RCT) (Griffin 1970) which included 2307 healthy people.

Excluded studies

We  excluded 41 studies (Belshe 1982; Belshe 1992; Belshe 2004a; Belshe 2004b; Clements 1991; DeVincenzo 2010; Doggett 1963; Dudding 1972; Falsey 1996; Falsey 2008; Fulginiti 1969; Gomez 2009; Gonzalez 2000; Greenberg 2005; Hamory 1975; Karron 1995a; Karron 1995b; Karron 1997; Karron 2003; Karron 2005; Langley 2009; Lee 2001; Lee 2004; Lin 2007; Lyons 2008; Madhi 2006; Munoz 2003; Murphy 1994; Paradiso 1994; Piedra 1995; Pierce 1968; Power 2001; Ritchie 1958; Simoes 2001; Tang 2008; Top 1971; Tristram 1993; Watt 1990; Welliver 1994; Wilson 1960; Wright 1976). Twenty-two trials were excluded because they did not evaluate the common cold as an outcome.

Risk of bias in included studies

The included RCT had overall low methodological quality. See Figure 2 and Figure 3 for a 'Risk of bias' graph and summary.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

The included trial was at unclear risk of bias for the random sequence generation and allocation concealment domains.

Blinding

The included trial was at unclear risk of bias for blinding of participants, personnel and outcome assessors.

Incomplete outcome data

The included trial was at unclear risk of bias for this domain.

Selective reporting

The included trial was at low risk of bias for this domain.

Other potential sources of bias

The included trial was at low risk of bias for this domain. This trial had sampling bias and bias in the presentation of data (Porta 2008).

Effects of interventions

See: Summary of findings for the main comparison Virus vaccines compared to placebo for preventing the common cold in healthy people

Results are based on one randomised controlled trial (RCT) (2307 healthy people). See Summary of findings for the main comparison.

Primary outcome

Incidence of the common cold

One trial (2307 participants, 27 events) showed that adenovirus vaccine was associated with a non-statistically significant reduction in the incidence of the common cold compared with placebo (risk ratio (RR) 0.95, 95% CI 0.45 to 2.02, P = 0.90) (Griffin 1970) (Analysis 1.1).

Vaccine safety

One trial (2307 participants, 27 events). This RCT did not report adverse events related to the live vaccine preparation.

Mortality related to vaccine

This outcome was not assessed by Griffin 1970.

Discussion

Summary of main results

This review found only one randomised controlled trial (RCT) and its critical appraisal does not support the use of any virus vaccines for preventing the common cold in healthy people. We did not find significant differences in the incidence of the common cold in people treated with adenovirus vaccines compared against placebo. Main clinical outcomes, such as mortality related to the vaccine, were not evaluated by Griffin 1970. This RCT did not find adverse events related to the live vaccine. The relative effect of any of the vaccines for viruses that cause the common cold remains unclear.

Overall completeness and applicability of evidence

Only one RCT was identified by our searches and it failed to detect statistically significant differences between the treatment groups.

When dealing with such neutral results, we need to keep in mind that 'absence of evidence' is not 'evidence of absence' (Altman 1995; Fermi Paradox 2012). The fact that this review did not detect any differences between the two intervention groups does not imply that placebo and adenovirus vaccine have the same effect on preventing the common cold. The first possible explanation is failure to determine an appropriate sample size (Green 2002; Schulz 1995), in this case due to small differences in the incidence of the common cold and few events in the comparison groups. In a remarkable paper from 28 years ago, Freiman 1978 suggested that "many of the therapies labelled as 'no different from control' in trials using inadequate samples, have not received a fair test" and that "concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials". In 1998, Moher emphasised that "most trials with negative results did not have large enough sample sizes to detect a 25% or a 50% relative difference" (Moher 1998). Moreover, it has been suggested that the most important therapies adopted in clinical practice have shown more modest benefits (Kirby 2002).

Quality of the evidence

The main source of bias in the included trial was the lack of detail in describing the generation of randomisation sequences and the concealment of allocation (Griffin 1970). The trial also lacked details regarding blinding processes. Our assessment of the risk of bias of the included study has been described previously and a summary can be found in Figure 3 and Figure 2. This study was not graded as providing strong evidence because there were small numbers of events in both groups, sample size calculations were not determined a priori (sample size bias), and there was unclear risk of selection bias and bias in the presentation of data (Porta 2008). See Characteristics of included studies for details. Additionally, Griffin 1970 had problems in the assessment of the main outcome (incidence of the common cold). These issues affected or distorted the internal validity. See Summary of findings for the main comparison which shows details of common cold incidence.

Potential biases in the review process

In the process of performing a systematic review, there is a group of biases known as 'significance-chasing' (Ioannidis 2010). This group includes publication bias, selective outcome reporting bias, selective analysis reporting bias and fabrication bias (Ioannidis 2010). Publication bias represents a major threat to the validity of systematic reviews, particularly in reviews that include small trials. However, we did an exhaustive search which included many RCTs that failed to evaluate common cold outcomes.

Agreements and disagreements with other studies or reviews

There are no other reviews or studies to compare with this Cochrane review.

Authors' conclusions

Implications for practice

This Cochrane review has found a lack of evidence on the effects of vaccines for the common cold in healthy people. Only one randomised controlled trial (RCT) was found and this did not show differences between the comparison groups. The results are based on only one trial with high risk of bias which involved 2307 patients and assessed adenovirus vaccine compared with a placebo. There is, therefore, insufficient evidence to support the use of vaccines for the common cold. Prescription of virus vaccines for preventing the common cold in these populations can neither be supported nor rejected, unless new evidence from large, high-quality trials alters this conclusion. Consequently, policy-makers, clinicians and academics should not yet recommend this virus vaccine. This Cochrane review does not provide evidence about other virus vaccines for preventing the common cold in healthy people.

Implications for research

This systematic review has highlighted a need for well-designed, high-quality randomised trials to assess the effectiveness and safety of virus vaccines to prevent the common cold in healthy people. The trials should include patient-based outcomes such as incidence of the common cold, vaccine safety and mortality related to the vaccine, and adverse events related to the vaccine administration. Future trials should be conducted by independent researchers and reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Ioannidis 2004; Moher 2010) and using the Foundation of Patient-Centered Outcomes Research recommendations (Anonymous 2012; Gabriel 2012).

Acknowledgements

The authors wish to express their thanks to the Acute Respiratory Infections Group's Managing Editor for her comments which improved the quality of this review. We also wish to express our thanks to Arturo Marti-Carvajal for his comments on this review. We thank the following people for commenting on this draft review: Theresa Wrangham, John Jordan, Viviana Rodriguez and Meenu Singh.

Data and analyses

Download statistical data

Comparison 1. Adenovirus vaccines versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of the common cold12307Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.45, 2.02]
Analysis 1.1.

Comparison 1 Adenovirus vaccines versus placebo, Outcome 1 Incidence of the common cold.

Appendices

Appendix 1. Differences between clinical characteristics of the common cold and influenza

FeatureCommon coldInfluenzaReferences
Aetiological agent> 100 viral strains; rhinovirus most common3 strains of influenza virus; influenza A, B, C

Gwaltney 2000

Gwaltney 1967

Heikkinen 2003

Roxas 2007

Thompson 2003

DDCP 2010

Site of infectionUpper respiratory tractEntire respiratory system
Symptom onsetGradual: 1 to 3 daysSudden: within a few hours
Fever, chillsOccasional, low grade (< 100ºF)Fever is usually present with the flu in up to 80% of all flu cases. A
temperature of 100°F or higher for 3 to 4 days is typically associated
with the flu
HeadacheFrequent, usually mildCharacteristic, more severe
General aches, painsMild, if anyCharacteristic, often severe and affecting the entire body
Cough, chest congestionMild to moderate, with hacking coughCommon, may become severe
Sore throatCommon, usually mildSometimes present
Runny, stuffy noseVery common, accompanied by bouts of sneezingSometimes present
Fatigue, weaknessMild, if anyUsual, may be severe and last 2 to 3 weeks
Extreme exhaustionNeverFrequent, usually in early stages of illness
SeasonYear around, peaks in winter monthsMost cases between November and February
Antibiotics helpfulNo, unless secondary bacterial infection developsNo, unless secondary bacterial infection develops

Appendix 2. Viral causes of the common cold

VirusEstimated annual proportion of casesReferences
Rhinoviruses

30% to 50%

During autumn 80%. Once considered to be limited to the upper airway, now recognised as an important cause for lower respiratory infections 

Arruda 1997; Gwaltney 1985; Heikkinen 2003; Lemanske 2005; Mäkelä 1998; Monto 1993; Regamey 2008
Coronaviruses

7% to 18% in adults with upper respiratory infections

Responsible for 2.1% of hospital admissions for acute respiratory tract infections in all age groups

Larson 1980; Lau 2006; Mäkelä 1998; Nicholson 1997
Influenza viruses5% to 15% Heikkinen 2003
Respiratory syncytial virus

In low-income countries, 15% to 20%

In hospital the proportion of children aged between birth and 5 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 6 months old

On average children aged 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

Berman 1991; Falsey 2005; Thompson 2003
Parainfluenza viruses

Acute respiratory infections cause 3% to 18% of all admissions to paediatric hospitals; 9% to 30% of these patients depending on the time of year

Parainfluenza viruses account for 17% of hospitalised illness-associated virus isolation

In low-income countries 7% to 10%

50% to 74.2% of croup cases are caused by this virus

Berman 1991; Denny 1983; Henrickson 2003

 

AdenovirusesIn low-income countries can be summarised as 2% to 4%  Berman 1991
Metapneumovirus10% short epidemic Esper 2003; Kahn 2003; Nissen 2002; Risnes 2005
Unknown20% to 30% Mäkelä 1998; Monto 1993

Appendix 3. Embase.com search strategy

#27. #23 AND #26 698 28 Mar 2011
#26. #24 OR #25 847,740 28 Mar 2011
#25. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEAR/1 blind*):ab,ti AND [embase]/lim 808,309 28 Mar 2011
#24. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim 239,310 28 Mar 2011
#23. #18 AND #22 10,015 28 Mar 2011
#22. #19 OR #20 OR #21 360,629 28 Mar 2011
#21. 'vaccination'/de AND [embase]/lim 59,591 28 Mar 2011
#20. vaccin*:ab,ti OR immuni*:ab,ti OR inocul*:ab,ti AND [embase]/lim 313,076 28 Mar 2011
#19. 'vaccine'/exp AND [embase]/lim 145,438 28 Mar 2011
#18. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 75,622 28 Mar 2011
#17. 'respiratory syncytial virus':ab,ti OR 'respiratory syncytial viruses':ab,ti OR rsv:ab,ti AND [embase]/lim 9,207 28 Mar 2011
#16. 'respiratory syncytial pneumovirus'/de OR 'respiratory syncytial virus infection'/de AND [embase]/lim 8,959 28 Mar 2011
#15. adenovir*:ab,ti AND [embase]/lim 32,848 28 Mar 2011
#14. 'adenovirus'/exp OR 'human adenovirus infection'/de AND [embase]/lim 22,001 28 Mar 2011
#13. coronavir*:ab,ti AND [embase]/lim 4,820 28 Mar 2011
#12. 'coronavirus'/de OR 'coronavirus infection'/de AND [embase]/lim 3,767 28 Mar 2011
#11. parainfluenza*:ab,ti AND [embase]/lim 3,478 27 Mar 2011
#10. 'parainfluenza virus 1'/de OR 'parainfluenza virus 2'/de OR 'parainfluenza virus 3'/de OR 'parainfluenza virus 4'/exp AND [embase]/lim 2,443 27 Mar 2011
#9. 'parainfluenza virus'/exp AND [embase]/lim 4,229 27 Mar 2011
#8. 'paramyxovirus infection'/de AND [embase]/lim 13 27 Mar 2011
#7. rhinovir*:ab,ti OR hrv:ab,ti AND [embase]/lim 6,932 27 Mar 2011
#6. 'rhinovirus infection'/de OR 'human rhinovirus'/de AND [embase]/lim 947 27 Mar 2011
#5. coryza:ab,ti AND [embase]/lim 197 27 Mar 2011
#4. 'acute upper respiratory infection':ab,ti OR 'acute upper respiratory infections':ab,ti OR 'acute upper respiratory tract infection':ab,ti OR 'acute upper respiratory tract infections':ab,ti OR (acute NEAR/5 (urti OR uri)):ab,ti AND [embase]/lim 308 27 Mar 2011
#3. 'viral upper respiratory tract infection'/de OR 'upper respiratory tract infection'/de AND [embase]/lim 10,980 27 Mar 2011
#2. 'common cold':ab,ti OR 'common colds':ab,ti AND [embase]/lim 2,073 27 Mar 2011
#1. 'common cold'/de OR 'common cold symptom'/de AND [embase]/lim 3,857 27 Mar 2011

Appendix 4. CINAHL (EBSCO) search strategy

S34 S23 and S33
S33 S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32
S32 (MH "Quantitative Studies")
S31 TI placebo* or AB placebo*
S30 (MH "Placebos")
S29 TI random* or AB random*
S28 TI (singl* mask* or doubl* mask* or tripl* mask* or trebl* mask*) or AB (singl* mask* or doubl* mask* or tripl* mask* or trebl* mask*)
S27 TI (singl* blind* or doubl* blind* or trebl* blind* or tripl* blind*) or AB (singl* blind* or doubl* blind* or trebl* blind* or tripl* blind*)
S26 TI clinic* w1 trial* or AB clinic* w1 trial*
S25 PT clinical trial
S24 (MH "Clinical Trials+")
S23 S18 and S22
S22 S19 or S20 or S21
S21 TI (vaccin* or immuni* or inocula*) or AB (vaccin* or immuni* or inocula*)
S20 (MH "Immunization")
S19 (MH "Vaccines+")
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17
S17 TI (respiratory syncytial virus* or rsv ) or AB (respiratory syncytial virus* or rsv)
S16 (MH "Respiratory Syncytial Virus Infections")
S15 (MH "Respiratory Syncytial Viruses")
S14 TI adenovir* or AB adenovir*
S13 TI coronavir* or AB coronavir*
S12 (MH "Coronavirus+")
S11 (MH "Coronavirus Infections")
S10 TI parainfluenza* or AB parainfluenza*
S9 (MH "Paramyxovirus Infections")
S8 (MH "Paramyxoviruses")
S7 TI hrv or AB hrv
S6 TI rhinovir* or AB rhinovir*
S5 (MH "Picornavirus Infections")
S4 TI (upper respiratory tract infection* or upper respiratory infection*) or AB (upper respiratory tract infection* or upper respiratory infection*)
S3 TI coryza or AB coryza
S2 TI common cold* or AB common cold*
S1 (MH "Common Cold")

Appendix 5. LILACS (BRIEME) search strategy

(mh:"Common Cold" OR "common cold" OR "common colds" OR coryza OR "Resfriado Común" OR "Resfriado Comum" OR "Coriza Aguda" OR "Upper Respiratory Tract Infections" OR "upper respiratory tract infection" OR "Infecciones del Tracto Respiratorio Superior" OR "Infecciones de las Vías Respiratorias Superiores" OR "Infecções do Trato Respiratório Superior" OR "Infecções das Vias Respiratórias Superiores" OR "Infecções das Vias Aéreas Superiores" OR "Infecções do Sistema Respiratório Superior" OR mh:"Picornaviridae Infections" OR "Infecciones por Picornaviridae" OR "Infecções por Picornaviridae" OR "Picornavirus Infections" OR mh:rhinovirus OR rhinovir* OR "Virus de la Coriza" OR "Virus del Resfriado Común" OR "Vírus da Coriza" OR "Vírus do Resfriado Comum" OR hrv OR mh:"Paramyxoviridae Infections" OR parainfluenza* OR mh:"Parainfluenza Virus 1, Human" OR mh:"Parainfluenza Virus 2, Human" OR mh:"Parainfluenza Virus 3, Human" OR mh:"Parainfluenza Virus 4, Human" OR mh:"Coronavirus Infections" OR coronavir* OR mh:coronavirus OR mh:"Coronavirus 229E, Human" OR mh:"Coronavirus OC43, Human" OR mh:"Coronavirus NL63, Human" OR mh:adenoviridae OR mh:"Adenoviruses, Human" OR mh:"Adenovirus Infections, Human" OR adenovir* OR mh:"Respiratory Syncytial Viruses" OR "Virus Sincitiales Respiratorios" OR "Vírus Sinciciais Respiratórios" OR "Virus Sincitial Respiratorio" OR "Vírus Sincicial Respiratório" OR mh:"Respiratory Syncytial Virus, Human" OR "respiratory syncytial virus" OR "Virus Humano Respiratorio Sincitial" OR mh:"Respiratory Syncytial Virus Infections" OR "Infecciones por Virus Sincitial Respiratorio" OR "Infecções por Vírus Respiratório Sincicial" OR rsv) AND (mh:vaccines OR vaccin* OR vacunas OR vacinas OR mh:d20.215.894* OR mh:vaccination OR vacunación OR vacinação OR mh:"Mass Vaccination" OR mh:immunization OR inmunización OR imunização OR mh:e02.095.465.425.400* OR mh:e05.478.550* OR mh:n02.421.726.758.310* OR mh:n06.850.780.200.425* OR mh:n06.850.780.680.310* OR mh:sp2.026.182.113* OR mh:sp8.946.819.838* OR immuni* OR inmuni* OR imuni*) AND db:("LILACS") AND type_of_study:("clinical_trials")

Appendix 6. Medical glossary

Term Definition Reference
Common coldThe common cold is a self limiting acute upper respiratory tract infection (URTI), characterised by rhinorrhoea, nasal congestion, sneezing, cough, sore throat, fever and malaise

Heikkinen 2003

 

VaccinationOf the vaccine: preparation of microbial antigen often combined with adjuvants, that is administered to the individuals in order to induce protective immunity against microbial infections. The antigen may be in the form of live, avirulent micro-organisms or purified macromolecular components of micro-organisms Abbas 2001
Immune systemThe collection of cells, tissues and molecules that mediate resistance to infections Abbas 2001
Cell-mediated immunityIs the arm of the adaptative immune response whose role is to combat infections by intracellular microbes. This type of immunity is mediated by T lymphocytes Abbas 2001
Antigenical variabilityMicrobes have evolved mechanisms to evade immunity. Many bacteria and viruses mutate their antigenic surface molecules and can no longer be recognised by antibodies produced in response to previous infection Abbas 2001
SerotypesAn antigenically distinct subset of a species of an infectious organism that is distinguished from other subsets by serologic (i.e. serum antibody) tests. Humoral immune response to one serotype of microbes, e.g. influenza virus, may not be protective against another serotypes Abbas 2001
Immune responsesOnce a foreign organism has been recognised, the system immune enlists the participation of a variety of cells and molecules to mount an appropriate response, to eliminate or neutralise the organism Goldsby 2000
Antigenic molecules

Any molecule capable of being recognised by an antibody or T-cell receptor. Any substance which elicits an immune response

Substance capable of inducing a specific immune response

Roitt 2004

 

Goldsby 2000

AllergensAn antigen that elicits an immediate hypersensitivity (allergic) reaction. Allergens are proteins, or chemicals bound to proteins, which induce IgE antibody production in atopic individuals Abbas 2001
Immunopotentiation

Non-specific immunostimulation given by various agents that can stimulate the immune response. It is believed that the mechanism of action is through some modification of local cytokines or growth of innate immune mechanisms

An increase in the functional capacity of the immune response

Gorczynski 2007
Opsonisation

The process by which particulate antigens are rendered more susceptible to phagocytosis

 

The process of attaching opsonins, such as IgG or complement fragments, to microbial surfaces to target microbes for phagocytosis

Goldsby 2000

 

Abbas 2001

Phagocytosis

Macrophages are capable of ingesting and digesting exogenous antigens, such as whole micro-organisms and insoluble particles, and endogenous matter, such as injured or dead host cells, cellular debris and activated clotting factors

 

The process by which certain cells of the innate immune system, including macrophages and neutrophils, engulf large particles (> 0.5 µm in diameter), such as intact microbes. The cell surrounds the particle by a cytoskeleton-dependent process, leading to formation of an intracellular vesicle called a phagosome, which contains the ingested particle

Goldsby 2000

 

Abbas 2001

History

Protocol first published: Issue 3, 2000
Review first published: Issue 6, 2013

DateEventDescription
16 March 2011New citation required and major changesProtocol taken over by a new team of review authors
26 February 2009AmendedProtocol withdrawn Issue 3, 2009

Contributions of authors

DSR conceived the idea for this review and drafted the protocol with comments from CVG and RHO.
DSR acts as guarantor for the review.
Daniel Simancas-Racines is a Ph.D. candidate at the department of Pediatrics, Gynecology and Obstetrics, and Preventive Medicine, Universitat Autònoma de Barcelona, Spain.

Declarations of interest

None known.

Sources of support

Internal sources

  • Universidad Tecnológica Equinoccial, Ecuador.

    Methodological

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Griffin 1970

  1. a

    RCT: randomised controlled trial
    SD: standard deviation

Methods

Design: double-blind, randomised controlled trial (2 arms)

Country: USA (1 site)

Clinical setting: Great Lakes Naval Training Center

Follow-up: 9 weeks basic-training period

Intention-to-treat: yes

Randomisation unit: patients

Analysis unit: patients

Participants

Great Lakes Naval Training Center, new recruits

Randomised: 2307 patients

Vaccines group: 1139 (49.3%)
Placebo group: 1168 (50.7%)

Patients receiving intervention: 1139

Vaccines group: 1139 (49.3%)
Placebo group: 1168 (50.7%)

 

Lost post-randomisation: 0%

Analysed patients:

Vaccines group: 1139 (49.3%)
Placebo group: 1168 (50.7%)

Age median (mean (SD)): did not report

Gender (number of men): did not report

Inclusion criteria:

1) 17 to 20 years of age
2) Great Lakes Naval Training Center, new recruits

Exclusion criteria: did not report

Interventions

Experimental group: the vaccines used were composed of orally administered live adenovirus 4, parenterally administered inactivated adenovirus 4, and parenterally administered inactivated adenovirus 4 and 7 preparations

Control group: placebo

Co-interventions:

a) 1.2 million units of benzathine penicillin G

b) polyvalent influenza vaccine

Outcomes

This RCT did not specify primary or secondary outcomes

Incidence of admissions of patients with respiratory illness (not only hospitalised patients)

  1. Acute undifferentiated respiratory disease (ARD)

  2. Common cold syndrome: an acute inflammation of the upper respiratory tract with coryza as a prominent feature and temperature, taken orally, of 100°F or less on admission

  3. Exudative pharyngitis

  4. Atypical pneumonia

  5. Viral exanthem

Toxic effects

Notes
  1. Trial registration: did not report

  2. A priori sample size estimation: did not report

  3. Conducted: from 19 February to 16 April, and observations continued to 20 June 1965

  4. Founder: "This investigation was supported in part by the Department of the Navy, research project MF 022.03.07-4014, and in part by the Public Health Service Vaccine Development Branch, contract 43-65-1031". (Page 981)

  5. Role of founder: "CAPT Robert O. Peckinpaugh, MC, USN; LCDR Wayne E. Frazier, MC, USN; and Willard E. Pierce aided in the design, conduct, and statistical interpretation of this investigation". (Page 981)

  6. Declared conflicts of interest: "The opinions and assertions contained here in are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the Naval Service at large." (Page 981)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Epidemiologic design of this study consisted of the random assignment of one half of the recruits..." (Page: 982)

Insufficient information to permit judgement of 'Low risk' or 'High risk'

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement of 'Low risk' or 'High risk'
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "Double-blind procedure was followed with paramedical personnel administering the appropriate vaccine or placebo to recruits on their third day after arrival at Great Lakes, just prior to initiation of basic training" (Page: 982)

Quote: "Placebo for the parenterally administered vaccines consisted of an injection of physiological saline, and that for the orally administered vaccine consisted of an identical appearing inert gelatin capsule" (Page: 982)

Comment: Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to permit judgement of 'Low risk' or 'High risk'
Selective reporting (reporting bias)Low risk

Comment: The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Quote: "...there was no observable toxic reaction to this new live vaccine preparation within the study design." (Page 985)

Other biasHigh risk

Bias in the presentation of data (Porta 2008)

Sampling bias defined as "Systematic error due to the methods or procedures used to sample or select the study subjects, specimens, or items (e.g., scientific papers), including errors due to the study of a nonrandom sample of a population." (Porta 2008)

Design bias: Quote: "Since recruits with the common cold syndrome rarely require hospitalizations, the effect of the adenovirus vaccines on this clinical entity can not be adequately evaluated." (Page 984)

Sponsor bias: Founder: Department of the Navy, research project MF 022.03.07-4014, and in part by the Public Health Service Vaccine Development Branch, contract 43-65-1031. Role of founder: Pierce aided in the design, conduct, and statistical interpretation of this investigation". (Page 981)

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial

Belshe 1982Non-RCT
Belshe 1992This RCT did not evaluate 'common cold'
Belshe 2004aThis RCT did not evaluate 'common cold'
Belshe 2004bThis RCT did not evaluate 'common cold'
Clements 1991Non-RCT
DeVincenzo 2010This RCT did not evaluate 'common cold'
Doggett 1963Non-RCT
Dudding 1972Non-RCT
Falsey 1996This RCT did not evaluate 'common cold'
Falsey 2008This RCT did not include healthy people
Fulginiti 1969Non-RCT
Gomez 2009This RCT did not evaluate 'common cold'
Gonzalez 2000This RCT did not evaluate 'common cold'
Greenberg 2005This RCT included patients less than 6 months of age
Hamory 1975Non-RCT
Karron 1995aThis RCT did not evaluate 'common cold'
Karron 1995bThis RCT did not evaluate 'common cold'
Karron 1997Non-RCT
Karron 2003This RCT did not evaluate 'common cold'
Karron 2005This RCT did not evaluate 'common cold'
Langley 2009This RCT did not evaluate 'common cold'
Lee 2001This RCT included patients less than 6 months of age
Lee 2004Non-vaccines interventions
Lin 2007This RCT did not evaluate 'common cold'
Lyons 2008This RCT did not evaluate 'common cold'
Madhi 2006This RCT included patients less than 6 months of age
Munoz 2003This RCT included pregnant women
Murphy 1994Update on vaccines topic
Paradiso 1994This RCT did not evaluate 'common cold'
Piedra 1995This RCT did not evaluate 'common cold'
Pierce 1968This RCT did not evaluate 'common cold'
Power 2001This RCT did not evaluate 'common cold'
Ritchie 1958Non-RCT
Simoes 2001Meta-analysis
Tang 2008This RCT did not evaluate 'common cold'
Top 1971This RCT did not evaluate 'common cold'
Tristram 1993This RCT did not evaluate 'common cold'
Watt 1990Non-RCT
Welliver 1994This RCT did not evaluate 'common cold'
Wilson 1960Non-RCT
Wright 1976Non-RCT

Ancillary