Changing epidemiology of COVID-19: potential future impact on vaccines and vaccination strategies

Figures & data

Table 1. Panel position and recommendations (with supporting references).

Topic	Position and recommendations	References
COVID-19 epidemiology	The decreasing trend in COVID-19-related deaths and hospitalizations, and the high levels of population immunity to SARS-CoV-2 indicate the likely end of the acute phase of the pandemic.	[14]
	SARS-CoV-2 will likely become an endemic pathogen in the human population.	[25,26]
	The definition of endemicity is suggested to be once the COVID-19 incidence settles to a non-zero level, as determined by waning immunity, transmission rate of variants, vaccination rates, seasonality, and human behavior. Finding this level of endemic ‘equilibrium’ is a delicate balance between the extent of mitigation measures enforced and the incidence of disease that societies will accept.	[17]
	Transition to endemicity may not occur at the same time in all regions, and there is a risk of reactivation of the pandemic in countries with high population density and limited healthcare access.
	Unbiased monitoring of SARS-CoV-2 transmission and infection rates should continue, via regular testing of sentinel populations or randomly selected representative samples of the general population, to allow for a comprehensive situational awareness.	[14]
	‘Wavelets’ (mini waves) may occur approximately every 3–4 months due to immune escape by new variants, resulting in milder infections rather than severe disease.	[21]
	The magnitude of the wavelets will likely decrease over time as basic immunity is established, with seasonal exacerbations occurring during colder weather.
	Variant surveillance should be maintained to identify SARS-CoV-2 mutations and variants that are able to evade the vaccine-induced antibody response and risk driving further waves.	[14]
SARS-CoV-2 evolution	COVID-19 resulting from Omicron infection is perceived to be less severe than previous variants [27,28]. However, current estimates of disease severity may be confounded by protection conferred by immunity from previous infection and vaccines.	[29]
	Continued emergence of more transmissible Omicron lineages and sublineages that are able to evade the vaccine-induced antibody response is likely, particularly due to increasing population immunity.	[7]
	A novel variant may still emerge, but widespread population immunity reduces the chance of a major increase in disease severity.	[30]
	Modeling to predict novel mutations is challenging, but has been beneficial in predicting epitope loss and potential vaccination targets.	[31–33]
	To date, most variants have been selectively driven by altered transmissibility or immune escape. Mutations outside of the receptor binding domain and those that affect viral infectivity and replication have not been extensively studied and require further research.	[6]
Burden of COVID-19	Estimates of infection rates may be affected by recent changes to testing capacities and practices, with many countries having discontinued most routine testing.	[15,16]
	The broader impact of COVID-19 vaccines, beyond protection from severe disease, needs to be better communicated. These benefits include the need to protect healthcare systems and avoid COVID-19-related absenteeism from school or work. The definition of post-acute COVID-19 sequalae (also referred to as long COVID), needs to be redefined and standardized, to include the duration of post-acute COVID-19 sequalae, and its specific symptoms, to aid our understanding of the disease and its management. There is no strategy or therapeutic approach to manage post-acute COVID-19 sequalae; potential management options need to be studied urgently among different subpopulations. Co-circulation of COVID-19, RSV, and influenza should be monitored closely to avoid a combined peak, which could overrun healthcare systems. Future combination vaccines should be explored to provide potential management options.
COVID-19 vaccine effectiveness and disease management	Reduced duration of protection with current COVID-19 vaccines is due to SARS-CoV-2 evolution and varying antigenicity, which is challenging for vaccine development. Learnings gained from the pandemic so far should be used to develop future COVID-19 vaccines with broader and more durable protection. Recent evidence suggesting lower relative COVID-19 vaccine effectiveness with emerging variants should be viewed cautiously. Original reference populations in clinical trials included infection- and vaccination-naïve individuals, whereas current populations are better protected due to previous natural infection or vaccination, which leads to improvements in efficacy data and adds bias to the data on vaccine effectiveness. Comparisons between the current population (which has some immunity due to natural infection and vaccinations) compared with the previous populations (no immunity due to no prior natural infection or vaccination) are imbalanced and introduce an unknown bias, as the infection rates are likely to be higher in unvaccinated individuals. This imbalance in infection rates presents a challenge when combined with the reduced level of national surveillance and reporting. There are still individuals who are not vaccinated and certain at-risk populations, for whom additional management options such as antiviral drugs are needed.
Future COVID-19 vaccination strategies	COVID-19 vaccination recommendations are likely to be continually updated for several more years using a variant-chasing approach and will focus on protection of at-risk groups (e.g. elderly individuals, and those with comorbidities or who are immunocompromised). Uptake of COVID-19 booster vaccinations has waned considerably over time. Local vaccination strategies must consider vaccine and booster coverage, along with the patient’s opinions and emotions regarding vaccination with COVID-19. If 12-month duration of protection can be demonstrated, administration of COVID-19 vaccines between September and October (in the Northern Hemisphere) of each year would be ideal to protect against the winter peak. Whether or not COVID-19 becomes seasonal, future COVID-19 vaccination strategies may be integrated into existing frameworks for seasonal influenza vaccination, independent of COVID-19 epidemiology, for economic reasons and to optimize vaccine uptake. An effective combined COVID-19/influenza vaccine may help to overcome vaccine hesitancy or booster fatigue.
Future COVID-19 vaccine development needs	Next-generation COVID-19 vaccines: Broad cross-reactivity against several SARS-CoV-2 variants is a key requirement, although this should not be at the expense of efficacy against existing variants. Longer duration of protection is required. However, demonstrating durability of protection with a new vaccine is challenging due to regular COVID-19 waves (every 3–4 months), the impact of vaccination timing and emerging variants, and confounding factors such as heterologous versus homologous vaccination and the different number of vaccine doses. Clinical studies assessing immunogenicity should consider the impact of natural immunity in a diverse population of individuals, since many individuals in current populations will have had previous natural infection(s). To increase global coverage and improve vaccine equality, next-generation COVID-19 vaccines must be accessible. Vaccines that are less expensive and have improved thermostability could benefit low/middle-income countries, which typically have higher temperatures and challenges with cold storage of mRNA vaccines. Intra-nasal vaccine administration could be a route to reducing viral transmission, along with additional benefits such as a decreased need for trained medical personnel, and less distress for children and individuals who have needle phobia. Pan-sarbecovirus vaccines: A pan-sarbecovirus vaccine targeting SARS-CoV-2 and other sarbecoviruses (e.g. SARS-CoV-1) with high zoonotic potential will be valuable for stockpiling and immunizing priority populations during the emergence phase of a new virus while a specific vaccine is in development. There are practical challenges involved with the development of pan-sarbecovirus vaccines, including extending shelf-life or stability (to maximize stockpiling capabilities), and regulatory considerations for how the assessment of clinical outcomes will be measured following vaccination against sarbecoviruses that are not currently in circulation.
	Development of a pan-betacoronavirus vaccine that provides broad functional protection against both SARS-CoV-2 and MERS would be challenging, due to differences between the viruses in host selectivity and tissue toxicity.	[34]
	Future vaccines in the US and EU: The formulations of COVID-19 vaccines were updated to a monovalent COVID-19 vaccine with an XBB-sublineage of the Omicron variant (XBB.1.5) and were implemented in Autumn 2023, for the start of the 2023/2024 vaccination program, following approval of emergency use in the US in September 2023; however, it is important that their superior performance characteristics and additional value compared with prior bivalent mRNA vaccines continue to be demonstrated (most importantly broad cross-reactivity and duration of protection).	[35–37]

COVID-19, coronavirus disease 2019; EU, European Union; MERS, Middle East respiratory syndrome coronavirus; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 2. Knowledge gaps and evidence generation needs.

Topic	Knowledge gaps and evidence generation needs	References
COVID-19 epidemiology	Robust active surveillance systems (including comprehensive and complementary data from different sources, e.g. wastewater surveillance, hospital admissions, and emergency department visits) are needed to provide accurate estimates of the numbers of cases to better inform the current epidemiology of COVID-19. COVID-19 seasonality needs to be defined, particularly when seasons start, to better inform vaccine recommendations and strategies. COVID-19 epidemiological modeling is increasingly complex. Future strategies may move away from a ‘one-size-fits-all’ model to the development and application of simpler models that are designed to address specific questions.
SARS-CoV-2 evolution	Additional knowledge is needed about mutations affecting viral infectivity and replication, as well as mutations in structural proteins other than the spike protein, such as the membrane, envelope, and nucleocapsid proteins. There is limited understanding of circulating SARS-CoV-2 and SARS-CoV-2 evolution in asymptomatic individuals, who are less likely to be tested and have viral sequencing performed to identify variants. Continued modeling is required for the purpose of predicting novel SARS-CoV-2 mutations and variants that could lead to new COVID-19 waves.
Burden of COVID-19	Cost-effectiveness modeling should consider the anticipated lifespan of a population, the effects of post-acute COVID-19 sequalae, as well as the impact of COVID-19-related mental health and work/school absenteeism.
	There is a need for further assessment of the benefits of COVID-19 vaccination for post-acute COVID-19 sequalae (also referred to as long COVID): comparing the characteristics of post-acute COVID-19 sequalae among individuals who are vaccinated versus unvaccinated and investigating the effect of COVID-19 vaccination in individuals with existing post-acute COVID-19 sequalae.	[38]
	Active surveillance should be maintained to monitor co-circulation of influenza, RSV, and COVID-19 to prepare for a potential combined peak.
COVID-19 vaccine effectiveness and disease management	Vaccine effectiveness should focus on a diverse population (including immunocompromised individuals) and outcomes used to measure vaccine effectiveness should include long-term efficacy. There are different reasons for waning immunity, which need to be better understood. Immunity translates into a longer duration of protection in some individuals compared with others, which needs to be better understood. Prediction modeling of vaccine impact should provide threshold levels for parameters such as efficacy and transmissibility.
Future COVID-19 vaccination strategies	A duration of protection of approximately 12 months from severe disease needs to be demonstrated in order to enable COVID-19 vaccinations to be annualized. Models that inform COVID-19 vaccination strategies must include social, behavioral, demographic, in-host (e.g. existing immunity), and socioeconomic factors, viral transmission and burden (asymptomatic cases, deaths, hospitalizations, major sequelae, post-acute COVID-19 sequalae), and genomic surveillance factors specific to an individual country/population. Models should be developed to inform COVID-19 vaccination requirements and strategies in special settings such as mass gathering events. Modeling may be used to further increase our knowledge of the benefits of mass vaccination, address issues of geographical vaccine equity, and calculate requirements for vaccine stockpiles.
Future COVID-19 vaccine development needs	Next-generation COVID-19 vaccines: Need to demonstrate: cross-protection against the full breadth of SARS-CoV-2 variants (Wuhan to Omicron) plus emerging variants, more durable and longer protection compared with bivalent mRNA vaccines, prevention or reduction in virus transmission as well as disease, safety/tolerability, and ease of use (i.e. no contraindications). Pan-sarbecovirus vaccines: Future pan-sarbecovirus vaccines would require clinical testing to at least Phase 2 for regulatory consideration. Extended shelf-life or stability would need to be demonstrated for the purpose of stockpiling for use in future pandemics.

COVID-19, coronavirus disease 2019; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

World Health Organization. 2023b. Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic [accessed 2023 Aug 7]. Available from: https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic.

 Google Scholar

Koelle K, Martin MA, Antia R, et al. The changing epidemiology of SARS-CoV-2. Science. 2022;375(6585):1116–1121. doi: 10.1126/science.abm4915

 PubMed Web of Science ®Google Scholar

Phillips N. The coronavirus is here to stay - here’s what that means. Nature. 2021;590(7846):382–384. doi: 10.1038/d41586-021-00396-2

 PubMed Web of Science ®Google Scholar

Contreras S, Iftekhar EN, Priesemann V. From emergency response to long-term management: the many faces of the endemic state of COVID-19. Lancet Reg Health Eur. 2023;30:100664.

 PubMedGoogle Scholar

Callaway E. COVID’s future: mini-waves rather than seasonal surges. Nature. 2023;617(7960):229–230. doi: 10.1038/d41586-023-01437-8

 PubMed Web of Science ®Google Scholar

Hyams C, Challen R, Marlow R, et al. Severity of omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalised adults: a prospective cohort study in Bristol, United Kingdom. Lancet Reg Health Eur. 2023;25:100556. doi: 10.1016/j.lanepe.2022.100556

 PubMedGoogle Scholar

Wolter N, Jassat W, Walaza S, et al. Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study. Lancet. 2022;399(10323):437–446. doi: 10.1016/S0140-6736(22)00017-4

 PubMed Web of Science ®Google Scholar

Nealon J, Cowling BJ. Omicron severity: milder but not mild. Lancet. 2022;399(10323):412–413. doi: 10.1016/S0140-6736(22)00056-3

 PubMed Web of Science ®Google Scholar

World Health Organization. 2023d. Statement on the update of WHO’s working definitions and tracking system for SARS-CoV-2 variants of concern and variants of interest [accessed 2023 Aug 12]. Available from: https://www.who.int/news/item/16-03-2023-statement-on-the-update-of-who-s-working-definitions-and-tracking-system-for-sars-cov-2-variants-of-concern-and-variants-of-interest.

 Google Scholar

Flahault A, Calmy A, Costagliola D, et al. No time for complacency on COVID-19 in Europe. Lancet. 2023;401(10392):1909–1912. doi: 10.1016/S0140-6736(23)01012-7

 PubMed Web of Science ®Google Scholar

Carabelli AM, Peacock TP, Thorne LG, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol. 2023;21(3):162–177. doi: 10.1038/s41579-022-00841-7

 PubMed Web of Science ®Google Scholar

Nature Editorial. This is no time to stop tracking COVID-19. Nature. 2022;603(7902):550. doi: 10.1038/d41586-022-00788-y

 PubMed Web of Science ®Google Scholar

Gov.UK. Press release. COVID-19 testing approach from April; 2023 [accessed 2023 Aug 5] Available from: https://www.gov.uk/government/news/covid-19-testing-approach-from-april-2023.

 Google Scholar

Liu J, Xie W, Wang Y, et al. A comparative overview of COVID-19, MERS and SARS: review article. Int J Surg. 2020;81:1–8. doi: 10.1016/j.ijsu.2020.07.032

 PubMed Web of Science ®Google Scholar

Nortate KI, Catahay JA, Velasco JV, et al. Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: a systematic review. eClinicalmedicine. 2022 Nov;53:101624. doi: 10.1016/j.eclinm.2022.101624

 PubMedGoogle Scholar