Addressing COVID-19 in the long-term – the role of immunisation

This briefing provides an overview of the latest advice on immunisation programmes in the short- and medium-term. It summarises publicly available evidence discussed at Scientific Advisory Group for Emergencies (SAGE) on factors to consider during the development of long-term immunisation strategies for SARS-CoV-2. It also discusses mechanisms to support the selection of future vaccines.

Latest announcements on SARS-CoV-2 vaccination policies

COVID-19 vaccines are the first line of defence in the Government’s ‘Living with COVID’ plan (published on 21 February 2022). The UK’s COVID-19 immunisation programme includes an enhanced booster vaccine programme (see the House of Commons Library briefing on ‘Covid-19 booster vaccines frequently asked questions’).

On 7 January 2022, the Joint Committee on Vaccination and Immunisation (JCVI) noted that ‘the main aim of the vaccination programme remains prevention of severe disease’. JCVI added that ‘alternative vaccines, including variant specific vaccines, may become available during 2022, and may be better suited to providing long-term protection against the Omicron variant, or other novel variants’.

On 21 February 2022, JCVI recommended as a precautionary measure a second booster dose in spring 2022 for adults aged 75 years and over, older adults who are residents in care homes, and immunosuppressed individuals aged 12 and over. This advice was based on available evidence that older adults are at higher risk from waning of vaccine-induced protection and that they are more likely to experience severe disease.

JCVI’s interim view on 22 February 2022 was that in autumn 2022 COVID-19 vaccines be indicated for high-risk groups, although details of the programme were not yet defined. JCVI also noted that ‘this advice should be considered as interim and for the purposes of operational planning’.

On 11 January 2022, the World Health Organization (WHO) Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) released an interim statement on COVID-19 vaccines in the context of the Omicron wave, highlighting that ‘a vaccination strategy based on repeated booster doses of the original vaccine composition is unlikely to be appropriate or sustainable.’

What needs to be considered for future vaccination strategies?

There is a broad consensus among scientists that SARS-CoV-2 will become an endemic virus and that there will always be new variants. This raises the question of what needs to be considered when developing immunisation strategies for SARS-CoV-2 in the medium- and  long-term.

The Joint Committee on Vaccination and Immunisation (JCVI) is responsible for providing advice on SARS-CoV-2 vaccination. As highlighted in the latest JCVI advice on 22 February 2022, ‘the need for, and timing of, vaccinations to protect against severe disease (hospitalisation and mortality) is influenced by various factors, including the degree of match between vaccine and virus, the duration of vaccine induced immunity and the timing of any future wave of infection[.] Natural immunity […] will become increasingly relevant as well.’

The Scientific Advisory Group for Emergencies (SAGE) has considered a series of briefings on long term immunisation strategies and related issues:

• The Vaccine Updates Group prepared a briefing on when and how to update SARS-CoV-2 vaccines. It was considered at SAGE 83 on 11 March 2021. At that time, Alpha was the dominant variant in the UK.
• The Vaccines Update Subgroup prepared a briefing on vaccine strain selection and immunity management for SARS-CoV-2. It was considered at SAGE 88 on 5 May 2021, at the beginning of the Delta wave.
• Academics prepared a briefing on the role of global vaccination in the emergence of new variants and the potential impact on UK public health. It was considered at SAGE 94 on 22 July 2021(before the emergence of the Omicron variant).
• Academics prepared a briefing on scenarios for the long term evolution of SARS-CoV-2. It was considered at SAGE 94 on 22 July 2021 and updated on 26 July 2021(before the emergence of the Omicron variant).
• Academics prepared a briefing on how long vaccines will protect against COVID-19. It was considered at SAGE 94 on 22 July 2021(before the emergence of the Omicron variant).
• The Scientific Pandemic Influenza Group on Modelling, Operational sub-group (SPI-M-O) prepared a consensus statement about considerations for medium- to longer-term epidemiological patterns of SARS-CoV-2. It was considered at SAGE 104 on 28 January 2022 (after the emergence of the Omicron variant).
• Academics prepared a paper about SARS-CoV-2 evolution scenarios. It was considered at SAGE 105 on 10 February 2022 (after the emergence of the Omicron variant).
• The New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) prepared an updated paper on Long term evolution of SARS-CoV-2. It was discussed at SAGE 105 on 10 February 2022 (after the emergence of the Omicron variant).

The factors that need to be considered when developing long term immunisation strategies can be divided into three broad categories: factors related to the virus, factors related to population immunity and factors related to vaccines. All these factors have a substantial level of uncertainty. Real world data is key in addressing this.

Factors related to the virus

It is currently not possible to predict the short- and long- term evolution of SARS-CoV-2 and the emergence of new variants (See POST’s Rapid Responses on SARS-CoV-2 virus variants and on the Omicron Variant). Future transmission patterns are also unclear.

As discussed during SAGE 94, the emergence of new variants is related to the levels of virus circulating in the population. There is a high confidence that emergence of variants that either are more easily transmissible, increase severity of the disease or escape the prior immunity (or a combination of these factors) represents the biggest health security threat for the UK. Increased severity, especially in combination with higher transmissibility, is a matter of concern. Global vaccination coverage has a role in preventing the emergence of new variants and a potential impact on UK public health, although it is likely that new variants arise in immunocompromised people, who do not show a good response to the vaccine.

As discussed during SAGE 104, it is very unpredictable how many variants will emerge, when, and what their characteristics will be (for instance, their severity). New variants may not derive from commonly circulating variants (such as Omicron or Delta) but may instead represent viruses that have evolved over time in a single immune supressed host with persistent infection.

Other uncertainties related to the virus in the long term include the interaction of SARS-CoV-2 with other respiratory viruses and the possible co-circulation of multiple variants with different characteristics and impact on different groups. Co-circulation of variants also increases the risk of novel ‘recombinant variants’. These are new versions of SARS-CoV-2 resulting from the combination of different variants (such as Omicron x Delta), derived from co-infected individuals. While the consequence of this cannot be predicted, there is a risk that novel recombinant viruses combine high transmissibility and high severity of the variants they originate from. A more detailed analysis of viral evolution scenarios is presented in the NERVTAG paper discussed at SAGE 105 on 10 February 2022.

The SPIM-O consensus statement prepared for SAGE 104 also discussed how SARS-CoV-2 patterns of transmission are still uncertain. Transmission of Alpha and Omicron began in the UK in the autumn and winter months, while transmission of Delta started in the spring.  Other respiratory viruses (e.g., influenza) have global seasonal patterns. Waves of infections mainly occur in autumn and winter months, while transmission decreases during summer months, with a reduction of contacts in indoors settings. This might also happen for SARS-CoV-2 in the long term.

Global seasonal patterns for SARS-CoV-2 are not yet fully established and they might take a decade or more to settle. Transmission patterns in the short to medium term will be influenced by international travel as well as global vaccination coverage (see Covax and global access to Covid-19 vaccines and UK and G7 commitments to donate Covid-19 vaccines).

Factors related to population immunity

There are a series of factors related to population immunity in the long term that are key in long term immunisation strategies. Questions to consider include:

1. how long immunity (both from natural infection and from vaccines) will last?
2. what aspects of the infection (asymptomatic/mild disease, hospitalisation or death) will immunity confer protection from?
3. how well will current vaccines (based on the ‘original’ SARS-CoV-2 first detected in Wuhan in 2019) work against new variants?
4. how precisely will we be able to assess and predict vaccine effectiveness before observing hospitalisations and deaths?

Real world data is providing initial evidence on some of these questions for SARS-CoV-2 (see below).

What is known so far about vaccine effectiveness?

The UK Health Security Agency (UKHSA) publishes weekly COVID-19 vaccine surveillance reports. They provide real-word data on the effectiveness of COVID-19 vaccines over time against infection, symptomatic disease, hospitalisation and mortality, for both the Delta and Omicron variants 

There are challenges in evaluating the effectiveness of COVID-19 vaccines two years into the pandemic. Vaccine effectiveness today is measured in comparison to a control population that is largely immune because they already had the infection. This has the effect of making vaccines look less effective than they actually are.

Another confounding factor related to calculating vaccine effectiveness against hospitalisation and deaths is the fact that Omicron is highly transmissible and can cause mild or asymptomatic infections. This means that if people are admitted to hospital for other reasons but happen to be positive for Omicron (often people are screened for Omicron during hospital admission and they might find out about an asymptomatic infection in this way), the admission may get labelled as being due to Omicron. This again has the effect of making vaccines look less effective than they are. There are several methods in place to exclude those cases, although none of them are perfect. A more granular analysis, including age groups and disease severity (e.g. need of oxygen) is needed to better estimate effectiveness.

Real world data shows from UKHSA that current COVID-19 vaccines are highly effective in protecting against hospitalisation and deaths but do not prevent transmission of the Omicron variant. Protection of two vaccine doses against infection and symptomatic disease wanes over time (medium-high confidence). COVID-19 boosters temporarily increase immune responses and vaccine effectiveness against infection and mild disease. For these reasons, there is consensus among scientists that protection against severe disease should remain the goal of vaccination strategies in the long term.

What is known so far about additional boosters?

Since the beginning of January 2022, Israel started administering a second booster dose (also called ‘fourth dose’) of the Pfizer/BioNTech vaccine to people over 60, health workers and immunocompromised patients. At the end of January, an Israeli government advisory panel recommended extending eligibility to all adults aged 18 and over.

Three vaccine doses provide high effectiveness against severe disease and there is preliminary evidence that a forth dose gives some additional benefits. A preprint (not peer reviewed) evaluated the effectiveness of a fourth dose of the Pfizer/BioNTech vaccine on confirmed SARS-CoV-2 infection and severe illness. It analysed data from 1,138,681 people aged over 60 years and eligible for the fourth dose between 15 January and 27 January 2022, while the Omicron variant was dominant.

The pre-print showed that the rate of confirmed SARS-CoV-2 infection was lowered by a factor of 2.0-2.1 in those who received a fourth dose at least 12 days earlier in comparison to those who received only three doses (administered more than four months earlier). The rate of severe illness was lowered by a factor of 2.4-7.6.  A limitation of the study is that it only analysed a time window of two weeks and that a longer follow up is needed to assess how long the protection from the fourth dose will last for.

It is unclear how this data can be translated to the UK. The two countries have different vaccination coverages and followed a different vaccination strategy. This includes different vaccines for the primary course of vaccination (in the UK many individuals received a University of Oxford/AstraZeneca vaccine as the first dose and Pfizer as second, while Israel mainly gave Pfizer vaccines) and a different dosing schedule.

What are the other unknowns with regards to population immunity?

As discussed in SAGE 104 and 94, an important aspect to consider in future vaccination strategies is how population immunity will change. For instance, ageing can affect an individual’s immune response, new diseases (such as cancer) can make people immunocompromised, SARS-CoV-2 infections (by different variants, before or after receiving booster doses) have an impact in shaping individuals’ immune responses.

The role of widespread circulation of infection, which may only cause mild or asymptomatic infection, in boosting immunity across the vaccinated population is likely to be important for sustaining and broadening population protection. However, natural infections are also likely to create vulnerabilities, potentially increasing the probability of severe illness in the vulnerable or higher numbers of long COVID cases (although see the latest UKHSA review on the effectiveness of vaccination against long COVID).

Moreover, more information is needed about the interaction between vaccine induced immunity and natural exposure in terms of the duration and breadth of protection. Further considerations on changes in population immunity are described in the SPIM-O consensus statement prepared for SAGE 104.

Correlates of protection (quantifiable signs, such as a certain level of neutralising antibodies, which could confirm that a person is protected from the virus) could help us to understand the level of protection within a population. However, any correlate of protection is an approximate correlate. There will always be exceptions because different individuals have different immune responses. Moreover, correlates of protection range, depending on whether they are considered with regards to protection from infection, transmission, severe disease or death and may be specific to the current vaccines.

There is some evidence (including from vaccine clinical trials) suggesting that certain levels of neutralising antibodies are correlated with short term protection against symptomatic infection from the Wuhan-variant, the Alpha variant and the Delta variant, but how this translates to future variants is unknown. Another important point to consider is that correlates of protection are evaluated at the population level. They therefore do not provide information about protection of an individual within the population. Moreover, information on robust correlates of protection against severe disease (the goal of current immunisation strategies) is not yet available

Another factor to consider is the complexity of the immune system. There are several players involved in the immune response against SARS-CoV-2 (see POST Rapid Responses on Immunity to COVID-19 for a description of the components involved). It is natural to observe a decrease of antibody levels over time (although no study shows immunity returning to zero) and components such as memory B cells and memory T cells are able to recognise and trigger an immune response for years after the first encounter. Antibodies also mature qualitatively over time and may localise at mucosal surfaces (the ‘entry route’ of SARS-CoV-2) to contribute to protection that is not currently being measured. Evidence on the role of cellular immunity (T cells) triggered by currently available vaccines in protecting against currently circulating variants is emerging. However, how well they will be able to react against future variants is unknown. Evidence suggests that T cells are able to recognise part of the virus that do not mutate as quickly as those which are recognised by antibodies.

Factors related to future SARS-CoV-2 vaccines and vaccination strategies

COVID-19 vaccines currently deployed in the UK are based on the original version of SARS-CoV-2 (first detected in Wuhan in 2019). Advances in vaccine technologies allow manufacturers to adapt COVID-19 vaccines quickly, and Pfizer/BioNTech and Moderna are currently testing Omicron-specific vaccines in clinical trials. However, there is a consensus among scientists that reacting to new emerging variants with updated vaccines is not a viable strategy, as vaccine development, approval, production and distribution will always be slower than future wave of infections.

When should vaccines be updated?

Current vaccines (based on the ‘original’ version of SARS-CoV-2) are highly effective against severe disease caused by the variants emerged so far. It is likely that effectiveness against severe disease will remain high if a similar degree of mutations accumulates in new variants. However, there is a higher level of uncertainty with regards to novel recombinant variants.

As discussed at SAGE 83 and SAGE 88, several considerations are needed to assess whether a vaccine update is needed, and when it should be undertaken. Surveillance of emerging variants, combined with a clear correlate of protection and a system to monitor immunity in the population are key to evaluate whether previous immunity in the population confers enough protection (See ‘Factors related to population immunity’).

Another important factor to consider is whether vaccines are used to protect from infection or severe illness.  Current vaccines do not appear to provide long term protection against infection or mild disease but there is consensus that protection against severe disease should remain the goal of vaccination strategies in the long term.

Vaccine update is associated with benefits as well as costs (for instance, in terms of manufacturing and distribution), but given the rapid emergence of successive variants so far, it may not be feasible to develop, licence and manufacture new vaccines in time for any meaningful response. On the other hand, the lack of an update could mean that a suboptimal vaccine would be used to protect against new variants, leading to lower vaccine effectiveness and further economic and social costs.

Vaccination strategies: what can be learnt from influenza?

As discussed SAGE 83 and SAGE 88, a process to inform SARS-CoV-2 vaccine selection and immunity management is needed to manage this virus in the long term (See the Vaccine Update Group briefing on vaccine strain selection and immunity management for SARS-CoV-2). This can be modelled on the system in place for influenza.

There is a well-established, formalised process to select new influenza vaccines every year, coordinated by the WHO worldwide. This system works well as there is a settled seasonal pattern for influenza, and its aim focuses on boosting a short-lived immunity ahead of the influenza season. Selection of new vaccines is based on surveillance of circulating viruses, monitoring of population immunity and estimates of vaccine effectiveness of different candidates. Consideration is also given to previous immunity of the population and related immunological phenomena (See the Vaccine Update Group briefing on vaccine strain selection and immunity management for SARS-CoV-2 for more details)

While the framework around influenza vaccines is a good model for SARS-Cov-2, it is still unclear how much SARS-CoV-2 vaccination can be modelled on influenza vaccination. From an operational perspective, the seasonal influenza vaccination programme could be combined with SARS-CoV-2 vaccination in the future. This could have several benefits, including a greater uptake of the two vaccines and reduced burden on healthcare systems (See WHO’s interim guidance on Coadministration of seasonal inactivated influenza and COVID-19 vaccines). Another key question is whether a framework around SARS-CoV-2 vaccines needs to be replicated in each country or whether it should be coordinated by the WHO.

Targeting vaccination strategies

Future vaccination strategies can target either the entire population or specific subgroups. As highlighted in the SPIM-O consensus statement prepared for SAGE 104, this will influence the distribution of the susceptible individuals within the population. Vaccinating only a specific subgroup of the population (for example, the elderly) will result in circulation of the virus in the unvaccinated (children and young adults). It is questionable, however, whether current vaccines can be used effectively to interrupt transmission in low-risk populations given the short-term protection conferred, and there are potential benefits of natural boosting in more vulnerable vaccinated populations.

As highlighted by the Vaccine Update Subgroup in SAGE 88, immunisation policies should also take into consideration how they might impact the long-term evolution of the virus. An important consideration is that vaccine-triggered immunity is likely to select for vaccine-escape variants. See the NERVTAG paper discussed at SAGE 105 for more information on scenarios involving vaccine-escape variants.

Other factors defining the pool of individuals susceptible to SARS-CoV-2 in the future are changes in the population (births and deaths), viral evolution and emergence of new variants and changes in population immunity.

Future COVID-19 vaccines: what’s next?

There are hundreds of SARS-CoV-2 vaccines under development. Different vaccine types (such as nasal spray vaccines, or whole inactivated virus vaccines) could induce different types of immunity, which could have different duration and may protect better than the current vaccines against infection and mild disease.

As discussed in a briefing prepared for SAGE 94 by the Vaccine Update Subgroup, future vaccination strategies could include the development of vaccines able to elicit a strong T cell response (that could be more resilient to new variants, although there are currently no T cell vaccines for any disease), or broadly protective vaccines. These include multivariant vaccines to target several SARS-CoV-2 variants circulating at the same time; universal coronaviruses vaccines designed to target all coronaviruses; or heterologous prime-boost strategies combining different vaccines during the primary course of vaccination (for example, a first dose with an mRNA vaccine and a second dose with a protein-based vaccine).

A key point for future vaccines discussed at SAGE 88 and SAGE 104 is the need to combine surveillance of variants with characterization of their features before they circulate widely in the population, in order to guide proactive design and selection of ad hoc vaccines. This is referred to as predictive vaccinology. A key consideration is that not all the new variants will spread widely in the population. For example, some variants (such as Mu) emerged in some geographical regions and then disappeared without spreading widely.

How to address the future?

As described by the Vaccines Update Subgroup briefing on vaccine strain selection and immunity management for SARS-CoV-2, the UK is well-placed to create a robust system for vaccine selection and immunity management to respond to SARS-CoV-2 in the long term. A key question is whether this system should be established at a single country level or at the global level, coordinated by the WHO.

Several elements of the infrastructure needed are already in place. These include the COVID-19 Genomics UK Consortium and UKHSA for virus surveillance; the UK Virology consortium for variant characterisation; and the UK COVID Immunology Consortium (UK-CIC) for SARS-CoV-2 immunology monitoring. Moreover, there are two technical advisory groups in the UK (the Variant Technical Group within UKHSA and the Vaccine Update Expert Advisory Group within the Vaccine Taskforce) who have the complementary expertise needed to identify the most effective vaccine for the future. Finally, the Joint Committee on Vaccination and Immunisation (JCVI) is responsible for providing advice on SARS-CoV-2 vaccination policies and update them in the medium and long term.

As highlighted in SAGE 88, there is a need to continue these initiatives, increase coordination and enhance their capabilities. Another important aspect identified is the need for integrated international systems (like those in place for influenza), coordinating public health systems worldwide with the support of regulators and manufacturers.

Disease and infection surveillance will continue to be of vital importance for generating real world data on how vaccines are and can impact on population protection. As highlighted in SAGE 105, the ONS Coronavirus infection survey is a critical tool for understanding the state of the epidemic.

Acknowledgements

POST would like to thank interviewees and peer reviewers for kindly giving up their time during the preparation of this briefing, including:

• Dr Mary Ramsay – Director Public Health Programmes (including Immunisation), UK Health Security Agency*
• The Immunology and COVID-19 Taskforce, British Society of Immunology*
• Professor Sir Andrew Pollard, Professor of Paediatric infection and immunity, Director of the Oxford Vaccine Group, University of Oxford*
• Professor David Goldblatt, Professor of Vaccinology and Immunology, Great Ormond Street Institute of Child Health, University College London*
• Professor Paul Kellam, Professor of Virus Genomics, Imperial College London
• Professor Derek Smith, Professor of Infectious Disease Informatics, University of Cambridge
• Professor Wendy Barclay, Professor of Virology, Imperial College London

*denotes people and organisations who acted as external reviewers of the briefing.

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