Overview

Distinguishing between influenza and COVID-19 requires a thorough understanding of their characteristics and behaviours. Resulting in a billion annual cases of seasonal flu,¹ influenza is a respiratory viral infection of the upper respiratory tract;² also a respiratory viral disease, COVID-19 is widely recognised to be caused by the SARS-CoV-2 virus,³ having caused an estimated sum of 670 million global cases by 25^th January 2023. Following its outbreak in December 2019, there had been speculations that SARS-CoV-2 would be no different from the influenza flu. As we know now, the COVID-19 pandemic will become a global nightmare, forever changing the appreciation of how we value human life. While there are similarities between influenza and COVID-19, both viral illnesses that have caused pandemics, there remain many stark differences regarding their genomic structure, mutation rate, and vaccines.

Genomic structure

While it is true that both are highly infectious viruses, they are not grouped in the same Baltimore classes. In 1971, Dr. David Baltimore, a highly accomplished biologist, proposed the Baltimore classification in his publication ‘Expression of Animal Virus Genomes’⁴ in which he identifies seven groups of viruses that each have their own method of replication and expression of their genetic material⁵. Influenza is classified as Baltimore class V (5), whereas SARS-CoV-2 is classified as Baltimore class IV (4).

The structure of the genetic material, better known as the genome, of a Baltimore class V virus is a single-stranded and negative-sense RNA. In order to replicate in a host cell, the influenza virus must first synthesise a positive-sense, single-stranded messenger RNA (mRNA) by using the negative-sense RNA as a template in the nucleus of the cell, now readable to the host cell; the mRNA carries its genetic information out to the ribosome of the cell where various proteins are produced to further aid viral infection. 

In contrast, the genome structure of a Baltimore class IV virus is a single-stranded, positive-sense RNA. Hence, the strands can act as mRNAs and directly express their first round of proteins⁷, streamlining the viral replication cycle. Though having a more time-efficient replication cycle has its perks in producing more viral particles faster, there is also an advantage to having a more complex replication cycle, as seen in Baltimore class V. The frequent template-switching seen in Baltimore class V viral replication introduces the opportunity for mutations to occur.⁸

Mutation rate

COVID-19 has a 23.9-fold lower mutation rate than influenza,⁹ predominantly due to its proofreading mechanism. It is true that mutations in both viruses have been crucial for their survival, with different variants affecting different regions of the world. 

COVID-19 variants 

The emergence of the different COVID-19 variants all occurred in a close time frame between 2020 and 2021 with a unique set of mutations. First identified in the United Kingdom in September 2020, the Alpha variant had mutations in the receptor-binding domain (RBD) N501Y and P681H and 144 deletions in the N-terminal domain (NTD), both found in the spike protein. In May 2020, the Beta variant emerged in South Africa with RBD mutations, most significantly N501Y, E484K and K417N. In January of the following year, the Gamma variant was identified in Brazil and garnered attention due to reports that it was 2.5 times more transmissible than previous variants; as well as NTD mutations, over half of the 22 mutations, were in the spike protein including L18F, N501Y, E484K and K417T. Simultaneously, the Delta variant emerged in India with noteworthy RBD mutations found in E484Q, P681R and L452R. As of now, the Omicron variant is the last of the variants identified in South Africa at the end of 2021; most concerningly, the Omicron variant had over 50 mutations that were predominantly associated with evading immune response or increasing the transmission rate.^10,11

Influenza variants

In the 20th century, there have already been three worldwide pandemics: the Spanish flu in 1918, the Asian flu in 1957, and the Hong Kong flu in 1968.¹² However, all were caused by different antigenic subtypes of the Influenza A variant. Due to a lack of a proofreading mechanism, the haemagglutinin and neuraminidase surface glycoproteins of the influenza virus can easily mutate via either antigenic drift (a point mutation) or antigenic shift (abrupt reassortment of genes between viruses) to produce new subtypes. As the most common variant, influenza A causes the most seasonal outbreaks before the variant influenza B.¹ The other two variants, C and D, are less common and non-endemic: influenza C typically causes mild infection, and influenza D primarily affects cattle.¹³

While the proofreading mechanism in COVID-19 helps establish a stable genome, it also prevents the host body from being overpopulated with viruses. Ultimately, viruses have a specific routine and set of equipment to infect and replicate in a host; as a result of lethal mutagenesis, a high mutation rate would overwhelm the virus with mutations to the point that it would produce a lack of or dysfunctional proteins, leading to the end of the viral population. However, antigenic shift and drift is a dominant mechanism for influenza to produce different subtypes of the variant, demanding the development of new and frequent vaccines. 

Vaccine 

Due to the high mutation rate of influenza, a new vaccine is introduced annually¹⁴ to combat seasonal outbreaks. In the UK, influenza vaccines are made accessible by the NHS during the peak of the outbreak in Winter and Autumn. People who are strongly advised to get vaccinated are:

1. Over the age of 65
2. Immunocompromised 
3. Pregnant
4. Carer of an elderly person or immunocompromised 
5. Have a long-term health condition (e.g. chronic kidney disease, liver disease, diabetes.)¹⁵

Since SARS-CoV-2 has a low mutation rate, the vaccines developed are long-lasting. Still, the spring vaccines are recommended for those who are:

1. Over the age of 75
2. Between the ages of 6 months and 74 years AND immunocompromised
3. Live in a care home for the elderly¹⁶

The approach to finding a vaccine during the COVID-19 pandemic was of utmost importance. To reduce transmission, the reproduction number (R₀) was used to understand the average number of secondary infections that would occur from an individual where everyone is susceptible. In the early phase of the pandemic, the R₀ was between 2 and 4.¹⁷ Since vaccinations aim to reduce the susceptible population, it did not take long until several pharmaceutical companies like Pfizer-BioNTech and Oxford-AstraZeneca began production. 

Vaccines come in many forms. While the traditional flu vaccines contain an inactivated form of the virus, mRNA vaccines are most common for COVID-19.^18,19 The inactivated form of the virus works to trigger an immune response when our white blood cells recognise influenza-specific surface proteins. In contrast, an mRNA vaccine involves the insertion of a small section of viral mRNA into a cell to produce and display the viral surface proteins (antigens), triggering an immune response. According to the CDC, the flu vaccines reduce the risk of illness in the general population by 40%-60%.²⁰ Similarly, 54% of people vaccinated for COVID-19 were less likely to get the infection between September and January.²¹ Though they cannot provide complete protection against all variants for all people, each vaccine has its own unique method of protecting public health.

Summary 

In summation, while influenza and COVID-19 are both respiratory illnesses that have had significant health impacts around the world, they still stand apart in several key characteristics: 

1. Influenza is a Baltimore class V virus, but SARS-CoV-2 is a Baltimore class IV virus, highlighting their genomic differences
2. Unlike influenza, SARS-CoV-2 has a proofreading mechanism, adding a layer of genomic stability
3. Due to a lack of a proofreading mechanism, influenza is highly prone to mutations, notably causing seasonal outbreaks annually
4. As a result, a COVID-19 vaccine is more long-lasting than an influenza vaccine as it does not require to be updated on a yearly basis
5. Though there are a few forms of vaccines for both, their most popular formats differ, where COVID-19 vaccines consist of the viral mRNA and influenza vaccines contain an inactivated form of the virus

Therefore, mistaking one for the other could lead to misconceptions and an oversimplified understanding of the behaviour of viruses, posing a threat to public health and safety worldwide.