Description of the condition

Although there is no standard definition for the common cold (see Appendix 1), it is generally defined as a spontaneously remitting infection of the upper respiratory tract (URT), characterised by a runny nose, nasal congestion, and sneezing. Other symptoms associated with the common cold include cough, malaise, sore throat, and fever (usually < 100 ºF/37.8 ºC) (Eccles 2009). A temperature of 100 ºF/37.8 ºC or higher for three to four days is typically associated with influenza and other respiratory diseases (see Appendix 2) (DDCP 2010). Despite the fact that the common cold is not considered to be a deadly disease, bacterial complications can lead to high morbidity and mortality (Giraud‐Gatineau 2020; Veiga 2021). 

The common cold is a disease of diverse aetiology (see Appendix 3) (Heikkinen 2003). Premature babies, children, the elderly, and other populations with comorbidities such as chronic lung diseases (chronic obstructive pulmonary disease), congenital heart disease, and asthma are more prone to viral infections that cause the common cold, including respiratory syncytial virus (RSV), human rhinovirus (HRV), parainfluenza, coronavirus, and adenovirus (non‐polio) (Johnston 2017; Lu 2020; Rubner 2017; Shibata 2018). Additionally, in humans, coronavirus such as the HCoV‐229E, HCoV‐OC43, HCoV‐NL63, and HCoV‐HKU1 strains are responsible for URT infections (URTI) associated with the common cold (Zumla 2016). It has been shown that 1% to 10% of the population is infected with the HCoV‐NL63 coronavirus annually (Szelazek 2017). Even the infectious agent SARS‐CoV‐2 can be associated with the common cold (Zimmermann 2020). The transmission of the common cold occurs through aerosols, direct contact with infected nasal secretions, or fomites (DeGeorge 2019; L'Huillier 2015; Reynolds 2016); the primary factors that contribute to the spread of this disease include poor hand hygiene, overcrowding, and interactions in places such as schools, day‐care centres, and between households (Adler 2018; Alexandrino 2016). 

The common cold is one of the most frequent illnesses experienced by humans. Children may experience up to 11 URTIs annually (Lambert 2007; Tang 2019), whilst adults experience an average of two episodes per year (Tomita 2012; Visseaux 2017). For instance, HRV is responsible for 50% to 80% of common colds, and it is an important cause of morbidity, reduced productivity, and inappropriate use of antibiotics (Kardos 2017; Warner 2019). Although there are few studies on the socioeconomic costs of the common cold, and most existing studies are problematic in terms of methodology (e.g. recall bias) for mainly being cross‐sectional studies on self‐reported surveys performed in a small or specific population, the impact on school and work absenteeism caused by common cold and the economic burden it causes cannot be overlooked (Dicpinigaitis 2015; Jaume 2020; Jaume 2021). In the United States, economic loss due to the common cold is estimated at more than USD 40 billion per year, including an estimate of 70 million workdays missed by employees suffering from a cold, 189 million school days missed by children, and 126 million work days missed by parents caring for children with a cold (Kardos 2017), all of which have an impact on productivity (Dicpinigaitis 2015). In Europe, the total cost per episode may be up to EUR 1102, of which 75% are indirect costs (Stjärne 2012). Additionally, there is a large expenditure due to inappropriate antimicrobial prescription and use for URTI (Tsuzuki 2020). 

Description of the intervention

There is no specific treatment for the common cold. Treatment is focused on easing the symptoms. Prevention is therefore essential to stop the spread of viruses that cause the common cold. In terms of preventive measures, studies have shown that simple measures such as handwashing and maintaining physical distance are relevant to all respiratory infections, but difficult to apply or enforce because, as time passes, motivation and compliance may decrease (Allan 2014; Jefferson 2020). Consequently, another method of prevention is vaccination. The development of vaccines for the common cold has been challenging because of the aetiological diversity of the disease and the antigenic variability of the common cold viruses (Glanville 2013; To 2017). The case of HRV remains a challenge for the public health and scientific communities due to technical, logistical, and fundamental biological difficulties (Stobart 2017). Unlike several human viruses, HRV vaccine must be able to elicit protective neutralising antibodies to potentially over 150 serologically distinct types spanning three different species (Ren 2017; Stobart 2017). For this reason, it is difficult to develop a vaccine that provides full protection (Stepanova 2019). Despite these challenges, recent attempts using rhinovirus‐derived VP1, a surface protein that is critically involved in the infection of respiratory cells, has demonstrated that with enough exposure and recombinant VP1 as an immunogen, cross‐serotype reactive antibodies can be generated (Edlmayr 2011; McLean 2012). The future of vaccine development for the common cold seems promising, considering that studies on virus genotyping such as HRV genotype are being published more frequently (Luka 2020; Ren 2017), and there is a rapid technological development of vaccines that include micro‐/nanoparticle material and recombinant technologies (Papadopoulos 2017).

Adenovirus is a recognised pathogen of the URT (Biserni 2020). Adenovirus serotype 4 (Ad4) and serotype 7 (Ad7) vaccines were used during immunisation programmes beginning in 1971. Unfortunately, their interruption triggered the re‐emergence of adenovirus‐produced diseases in crowded locations. An example of this reappearance was documented in US military training sites, where Ad4 accounted for 98% of all diagnoses (Russell 2006). The development and deployment of AdV‐4 and AdV‐7 vaccines is essential in controlling AdV‐4‐ and AdV‐7‐related URTI (Collins 2020). 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 large immune response in the studied populations. For instance, a study examining the duration of the neutralising antibody response generated from a live oral AdV‐4 and AdV‐7 vaccine showed that, regardless of pre‐vaccination serostatus, participants developed a significant antibody response which persisted for at least six years after vaccination (Collins 2020).

RSV is an important cause of respiratory infection in older adults, and almost all children have been infected with RSV by the age of two; due to incomplete and short‐lived natural immunity, repeated RSV infections occur throughout life (Williams 2020). The development of an RSV vaccine has been difficult due to antigenic variability, especially in proteins F and G. However, a first‐in‐human phase 1 trial has been reported to evaluate the safety and immunogenicity of an experimental RSV vaccine of Ad26.RSV.preF (a replication‐incompetent adenovirus‐26 vector encoding the F protein), which is administered intramuscularly 12 months apart in healthy adults aged ≥ 60 years old (Williams 2020). There have also been concerns of enhanced respiratory disease (ERD) after vaccination with the formalin‐inactivated RSV vaccines in the 1960s, in which patients showed X‐ray evidence of severe pneumonia and bronchiolitis, in addition to immunopotentiation induced by a T helper (Th)‐2 and Th17 T cell responses with the enrolment of T cells, neutrophils, and eosinophils causing inflammation and tissue damage (Rey‐Jurado 2017). Current vaccine candidates, especially those designed for infants and children, whose immune systems are still immature, must therefore be safe and avoid these immunologic features of ERD (Mazur 2018).

One RSV immunisation approach is the development of a vaccine for pregnant women, since it has been demonstrated that RSV‐neutralising antibodies are transferred from the pregnant woman to the foetus through the placenta (Chu 2014). A clinical trial in which healthy pregnant women received either an intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo, showed that during the first 90 days of life, infants with RSV had a significantly lower number of respiratory tract infections (1.5%) compared to the placebo group (2.4%). However, to tag the vaccine as successful in terms of efficacy, its possible benefits with respect to other endpoint events have to be demonstrated (Madhi 2020). Another phase II clinical trial evaluated the tolerability and safety of RSV fusion (F) protein nanoparticle vaccine compared to placebo in 50 healthy third‐trimester pregnant women and their infants (Muňoz 2019). The trial demonstrated that the vaccine was well tolerated with no differences on safety outcomes other than expected short‐term reactogenicity in women who received the active vaccine. In addition, transplacental antibody transfer ranged between 90% and 120% across assays for infants of the vaccinated group of women (Muňoz 2019).

Regarding parainfluenza, there is still no approved vaccine available. However, the intranasal administration of two doses of a live‐attenuated human parainfluenza virus type 3 HPIV3‐cp45 vaccine seems promising, as it has been shown to be well tolerated and immunogenic in seronegative children over six months of age (Karron 2011). 

How the intervention might work

Vaccines work by inducing an immune response, such as an antibody response that interferes with a pathogenic invasion and prevents their adherence to epithelial cells through opsonisation, phagocytosis, and other mechanisms (Pichichero 2009; Wooden 2018). A correlate of protection to a pathogen is a measurable sign that a person is immune after vaccination, and can either be absolute or relative (Plotkin 2020). There may also be more than one correlate of protection for a disease, known as 'co‐correlates' (Plotkin 2020). The immune memory is a critical correlate (effector memory for short‐incubation and central memory for long‐incubation diseases), and cell‐mediated immunity can operate as a correlate or co‐correlate of protection against a disease (Plotkin 2010). However, some vaccines only have surrogates for an unknown protective response, which are easy measurements but not functional (Plotkin 2010). For instance, as there is no correlate of protection for the development of HRV vaccines, serum IgA is used as a surrogate marker for studies on all live attenuated HRV vaccines to demonstrate vaccine take (Armah 2016).

Studies suggest that vaccines that mimic natural infection and take into account the structure of pathogens seem to be effective in inducing long‐term protective immunity (Kang 2009). Different types of vaccines against respiratory viruses already exist, but all have been focused on decreasing the incidence of lower respiratory infections. Traditionally inactivated or live attenuated viruses are used. However, there are promising approaches that use micro‐/nanoparticles material and recombinant technologies that produce a broad immunogenic, reproducible, safe, and often self‐adjuvating response (Gomes 2017; Papadopoulos 2017).

Why it is important to do this review

Although the common cold is self‐limiting with symptoms often lasting up to 10 days, it is the most common acute illness in industrialised countries with a very high incidence, presenting several episodes per person a year, as well as being one of the main causes of primary care consultations (DeGeorge 2019; Jaume 2020). Despite being generally mild, the common cold can occur with other respiratory illnesses, which can predispose susceptible individuals to potentially serious complications. Vaccines could therefore be used to reduce the prevalence of the disease around the world and decrease primary care consultations that might saturate healthcare systems.

The socioeconomic burden from the common cold has not been fully studied, and the few studies published in this area mainly have methodological limitations. However, it has been demonstrated that the common cold can lead to work and school absenteeism as well as having an impact on productivity and healthcare costs (Dicpinigaitis 2015; Jaume 2021; Kardos 2017), which could also be reduced by preventing the illness through vaccine use, if effective.

Furthermore, if randomised controlled trials demonstrate that there is an effective and safe vaccine to prevent the common cold, scientists could continue researching this field.