What is the nature of the immune response?
The body uses immune responses to defend itself against bacteria and viruses, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Covid-19. SARS-CoV-2 is a pathogen, an infectious organism that can produce disease. Pathogens contain unique antigens (molecules on their surface), which bind to and infect cells in the body. Antigen detection alerts the body to a threat and prompts the immune response.
- Innate immune responses are generalised responses that react to any antigens and involve several types of specialised cells and signalling chemicals.
- Adaptive memory immune responses respond to specific antigens, based on immunological memories formed from earlier infections or vaccinations. If somebody is exposed to the same infection again, their body can offer enhanced protection. These responses can take up to three weeks to develop and vary in strength and longevity. The adaptive immune response involves white blood cells (B cells and T cells). B cells produce antibodies, which are antigen-specific proteins produced to help fight infection. T cells can be ‘killer cells’ that destroy the body’s own infected cells, or ‘helper cells’ that stimulate the development of B cells or killer T cells.
SARS-CoV-2 encodes four main structural proteins, including the spike protein. The spike protein is an antigen that protrudes from the surface of the virus and latches on to human cells in the respiratory tract.
Infected cells release interferon proteins, which can prevent the virus from leaving a cell, or from infecting other healthy cells. Interferons can reduce the production of viral molecules and engage T cells to neutralise infected cells. Antigens also activate B cells to produce antibodies, which attach to virus proteins (such as the spike) and prevent them from entering cells. Antibodies can also help other cells and molecules find and destroy infected cells.
SARS-CoV-2 can evade the body’s immune response. Compared with most other RNA viruses, SARS-CoV-2 produces more proteins, which can reduce signals produced by the antigen to avoid T cell detection. Different variants can result in mutations to the spike protein, which may reduce antibody recognition and the effectiveness of adaptive immune responses. T cells may provide a more robust response across variants, as they can recognise parts of the virus that do not mutate as quickly. However, T cell recognition may also decline across mutations.
T cells induced by other coronaviruses (such as common colds) may provide some protection against SARS-CoV-2. This has been suggested from incidental findings in people who evaded infection in multiple studies, including the first UK Covid-19 human challenge study. Future work with larger samples would be needed to support this claim.
Harmful outcomes from the immune response to Covid-19
Some people experience severe Covid-19 symptoms, such as respiratory distress. These symptoms occur during later stages of infection, driven by the body’s own immune response. Understanding how the immune response causes severe or prolonged health outcomes is important for deciding prevention and treatment.
Most people do not experience severe symptoms. One study of 2.3 million adults in England found that 7.1% were hospitalised and 2.3% died within 28 days of testing positive for Covid-19. These rates are likely lower at the time of writing, since the data was collected between October 2020 and April 2021 before many people had acquired immunity through infection or vaccination. Further, the current dominant Omicron variant is less likely to result in hospitalisation compared to previous variants.
Symptom severity has been attributed to irregular immune responses, including delayed T cell responses, ineffective interferon responses or hyperactive inflammatory responses, such as cytokine storms. Cytokine storms occur when T cells over-produce inflammatory molecules and release them into the bloodstream too quickly. This can result in tissue damage, multiple organ failure, and death. Infection can prompt the production of autoantibodies, which harm the body’s own protective cells. One study estimated that autoantibodies may contribute to around 20% of Covid-19 related fatalities.
Persistent symptoms, described as ‘long-Covid’, have been associated with immunological dysfunction 6-8 months after infection, shown by highly active innate immune cells and interferons, but low numbers of T and B cells. Low T cells were particularly prevalent in older adults who experienced ill-health and fatigue. In some cases, long-Covid complications may result in long-term autoimmune conditions such as multisystem inflammatory syndrome or Guillain-Barré syndrome. However, this is unlikely for most people.
Immunity estimates in the UK population
Population immunity is estimated by measuring blood antibody levels in a sample of the population, as SARS-CoV-2 antibodies indicate that somebody has previously been infected with, or vaccinated against, Covid-19. However, antibodies are only one part of the immune response and may not prevent future infection. The Office for National Statistics (ONS) publishes population estimates the percentage of the population with detectable antibodies, modelled on blood tests from randomly selected subsamples, weighted by age, sex, region, and ethnicity.
According to the ONS, an antibody concentration of at least 179 nanograms per millilitre (ng/ml) of blood offers a ‘sufficiently strong antibody response’ to offer some protection against infection with the Delta variant (the main circulating variant between March – November 2021). There is insufficient evidence to determine levels required for Omicron (the most dominant variant since November 2021).
Current estimates
At the end of November 2022, the percentage of adults estimated to have antibody concentration levels that could offer a strong antibody response (179ng/ml) was between 95.9-97.4% across England, Wales, Northern Ireland and Scotland. Antibody concentrations were estimated in around 72.4% of 8–11-year-olds (an increase over the past year), and 90.7% of 12–15-year-olds. The ONS estimates that most people have antibody concentrations of at least 800 ng/ml, and a smaller percentage of the UK population will have much higher antibody concentrations (6000 ng/ml and above). Monitoring high antibody levels is a useful early indicator for antibodies waning over time. People aged 65 years old and over are more likely to have higher concentrations, due to the recent booster vaccination scheme.
How does the immune response differ across people?
Age is the strongest risk factor for severe health outcomes from Covid-19. Children have a faster and more effective innate immune response to SARS-CoV-2 in their nasal fluid, which helps to clear the virus quicker. Children also have higher levels of innate immune cells in their upper respiratory tract, which can provide a stronger defence before infection occurs. Despite a more robust response, children are more prone to reinfection. Compared to adults, children do not produce as many types of antibodies in response to the virus, which reduces adaptive immunity protection.
Some people are more likely to have immune response irregularities that lead to severe Covid-19 symptoms. This includes groups with certain underlying health conditions, including diabetes and obesity. Severe health outcomes are more likely in immunocompromised people with a weakened immune system, including people receiving treatment for HIV or AIDS, certain types of cancer or organ transplants. An analysis of 17 million England patient records found that people with some pre-existing inflammatory immune conditions (such as rheumatoid arthritis) were at greater risk of death or hospitalisation as result of Covid-19. This risk has also been observed in an international cohort study of 133,589 patients.
Researchers are examining the similarities and differences in the immune response when someone has been infected or vaccinated. Immunity protection depends on multiple factors, including the level of exposure (viral load), the variant responsible for initial and subsequent infections, and vaccination status. This can make it difficult to make comparisons, as earlier research may reflect times when fewer people had been vaccinated, and fewer variants had emerged.
Immune responses after infection and vaccination
Immune responses to reinfection
A systematic review of 12 million people found that immunological memory for SARS-CoV-2 was evident within 90% of those infected after 6-8 months. Prevalence of antibodies (90.4% of population), B memory cells (80.6% of population), and T helper cells (91.7% of population) was high. However, concentration levels within individual people were low due to waning protection. Within the total combined sample, 0.2% were reinfected within this period.
People are less likely to be reinfected if they are initially exposed to a higher viral load, or experience symptoms within 35 days of their first infection. One study found that adapted T cell responses were 50% higher in those that had experienced symptoms during the first infection, compared to those who were asymptomatic.
Reinfection risks have varied across the pandemic. The ONS reported that previous infection reduced reinfection risk by 65% when the Alpha variant was most dominant, (December 2020 – May 2021), and 71% when the Delpha variant was most dominant (May 2021 – August 2021). In comparison, Imperial College London estimated that previous infection reduces the risk of reinfection by the Omicron variant by 19%.
According to the ONS, 93.4% of recorded reinfections occurred when the Omicron variant was most dominant (December 2021 onwards). Infections from previous variants (such as Alpha) appear to produce a weaker antibody response against Omicron. Infection with Omicron provides enhanced B and T cell immunity against earlier variants, however, it provides much lower immunity protection against reinfection with Omicron itself, even in those who have been triple-vaccinated.
Immune responses following vaccination
Vaccines enable people to develop an adaptive immune response to SARS-CoV-2, without getting infected. There are six Covid-19 vaccines approved for use in the UK, and the three currently distributed are Novavax (Nuvaxovid), Moderna (Spikevax) and Pfizer-BioNTech (Comirnaty). All three vaccines require at least a primary course of two doses, and protection can be extended and increased by an additional booster dose.
In January 2023, the UK Health Security Agency (HSA) reported that vaccines reduce the risk of developing symptomatic illness by 45-70% two weeks after receiving two doses. This reduces to 15% or less after 25 weeks. A third dose offers peak protection of 60-75% 2-4 weeks after administration, usually with no effect against symptomatic illness after 20 weeks. A third dose also offers temporary protection against reinfection.
The greater benefit of vaccination is that it reduces the risk of severe disease, hospitalisation and death. All vaccines increase levels of protection against hospitalisation across all variants. The UK HSA estimates that protection against hospitalisation peaks at 83.9% in 18–64-year-olds, reduced to 45.5% after 25-39 weeks. Protection for those aged over 65 peaks at 89.5% before waning to 60.7% at 40 weeks. Protection was highest for the most severe hospital outcomes (including ventilation and admission to intensive care).
All vaccines have shown at least 90% protection against death with Alpha and Delta variants, with limited waning over time. A recent study of the Omicron variant estimated that vaccine effectiveness against death was around 50% in those aged 50 and over, 25 weeks after the second dose. An additional booster vaccination provided effectiveness of 93.6% after two weeks and 87.6% aften ten weeks.
Vaccination protection against long-Covid is less understood, partially because long-Covid does not have a clear definition. One nationwide medical record study in Israel showed that vaccination significantly reduced the likelihood of long-term breathing difficulties. Further systematic reviews have suggested that vaccination reduces the risk of developing persistent symptoms, with one study suggesting that two vaccine doses before infection reduces the risk of symptoms after 28 days.
Prevention strategies
Vaccination
Covid-19 vaccines remain the first line of defence in the Government’s ‘Living with Covid’ plan. Vaccines protect the individual and benefit the wider population by reducing the risk of transmission. By the end of 2022, 93.6% of the UK population (aged 12 and over) had received their first dose of the vaccine, 88.3% had received a second dose, and 70.2% had received a third or booster dose.
Following recommendations from the Joint Committee on Vaccination and Immunisation (JCVI), the Government introduced a further vaccine booster programme in September 2022. The main aim was to increase protection from severe illness from targeted groups most at risk, including frontline healthcare workers, those in care homes, people who are immunosuppressed and those aged 50 years and older. The programme was scheduled ahead of the winter months when transmission of Covid-19 and influenza tends to be higher.
Ahead of the autumn schedule, the Medicines and Healthcare products Regulatory Agency (MHRA) approved Moderna and Pfizer/BioNTech bivalent vaccines, which stimulate an immune response against antigens from the original SARS-CoV-2 strain and the more recent Omicron B.1 variant. These vaccines are the single type of vaccine being deployed during the autumn booster schedule, following JCVI recommendations to prioritise timeliness and simplicity to reach the maximum number of people ahead of winter. Covid-19 vaccines can be given at the same time as season influenza vaccines and most other vaccinations, which can reduce costs and improve distribution efficiency. The Welsh Government introduced a combined Winter Respiratory Vaccination Strategy, which aimed to offer vulnerable groups both vaccines at the same appointment, with the target of achieving 75% uptake for both vaccines. In Scotland, almost 90% of people who have received a Covid-19 booster vaccine also received an influenza vaccine at the same appointment.
Over 13 million people received the autumn booster dose in England by the end of January 2023, including the majority of those aged over 60. In Wales, almost 1.1 million people have received the autumn booster, comprising the majority of most of the targeted groups. Autumn boosters have been administered to almost 2m people in Scotland (72% of those eligible), and over 510,000 people (63.7% of those eligible) in Northern Ireland.
The 2022/23 vaccine booster programme ended in mid-February. The JCVI has advised that the primary vaccine course should no longer be offered to people under 50 years old without underlying health conditions, in favour of a more targeted approach towards those at risk of severe illness.
In July 2022, the Coalition for Epidemic Preparedness Innovations announced $30 million to fund clinical trials for a new nanoparticle vaccine, which could offer protection against future SARS-CoV-2 variants, as well as future coronaviruses that may emerge from animal populations. This vaccine contains fragments of the SARS-CoV-2 spike protein, combined with seven other types of coronaviruses.
Researchers are also developing mucosal vaccines (administered through the mouth or nose), which could potentially prevent Covid-19 before infection occurs. These vaccines are in the early stages of development. Recent results from the first phase of the AstraZeneca human clinical trial indicated that further developments are required for effective protection.
Drug therapies
Antiviral drugs can mitigate and/or prevent SARS-CoV-2 infection by suppressing the virus’s ability to replicate within cells. These treatments can be used to protect people with severely compromised immune systems from SARS-CoV-2 infection or Covid-19 disease, especially those that are higher risk because they cannot be vaccinated, or for whom vaccines are ineffective. People deemed to be at high-risk may be prescribed antiviral drugs to take as soon as they test positive for the virus or if they come into contact with someone who is infected.
Antibody treatments can mimic or enhance immune system functions. Antibody treatments need to be repeated every few months (as the antibodies decay with time), and treatments may become less effective if the targeted part of the virus mutates beyond recognition of the antibody. Therefore, vaccines and drug therapies must be continually assessed for their effectiveness against new variants. The MHRA has approved two antibody treatments, which bind to specific parts of the spike protein and prevent the virus from entering the cell: Sotrovimab (Xevudy, GSK and Vir Biotechnology) and Evusheld (AstraZeneca).
Sotrovimab is sometimes used to treat high-risk adults and children over 12 years old who are already infected with Covid-19. It is no longer widely used within the NHS, due to low effectiveness against the Omicron variant. However, Sotrovimab is still administered to patients who are unable to take antiviral medicines.
Evusheld is an antibody treatment that can prevent and treat COVID-19, approved by the MRHA for preventative use. However, it is not available on the NHS, and must be purchased privately (over £1200 for the recommended dose). Organisations such as Blood Cancer UK and Leukaemia Care have advocated that immunocompromised groups need better access to drug therapies, due to the mental, physical, and financial consequences of shielding.
The UK Government decided not to purchase Evusheld, following advice from advisory group RAPID C-19 (Research to Access Pathway for Investigational Drugs) that Evusheld has lower effectiveness against newer variants. Evusheld was referred to the National Institute for Health and Care Excellence (NICE), who determined limited clinical and cost-effectiveness in preventing newer Covid-19 variants. The report also announced the development of a new review process for Covid-19 treatments, which will enable patients to access treatments more quickly.
Acknowledgements
POST would like to thank members of the British Society for Immunology expert taskforce on Immunology and COVID-19, who acted as external peer reviewers in preparation of this article.
Photo by PIRO from Pixabay
