Effectiveness of fourth dose COVID-19 vaccine against the Omicron variant compared to no vaccination

In response to enhanced immune evasion properties of the Omicron SARS-CoV-2 variant and waning COVID-19 vaccine effectiveness (VE), several jurisdictions have rolled out fourth dose vaccination programs. Using a system of logistic regression equations and VE estimates for a fourth dose relative to a third dose reported in an Israeli study, we estimated absolute vaccine effectiveness for third and fourth doses of mRNA COVID-19 vaccine (c.f. no vaccination) against Omicron, by clinical outcome. We found that a fourth dose restores or even enhances protection conferred by a third dose at the same time since vaccination.

Relative contributions of vaccination and previous infection to population-level SARS-CoV-2 immunity over time: a simulation modelling study

Population-level immunity to SARS-CoV-2 directly impacts the incidence of COVID-19 morbidity and mortality. Understanding how this immunity is likely to change over time in the context of future vaccination schedules and emerging SARS-CoV-2 variants is critical to inform pandemic policy. This study simulates population-level COVID-19 immunity (including relative contributions of vaccination and previous infection) in Victoria, Australia over 18 months using an agent-based model and logistic regression equations that predict immunity and waning following vaccination and/or infection. Previous infection was found to drive most immunity against infection even with ongoing regular vaccination, however a greater proportion of overall immunity against mortality was accounted for by vaccination. Although previous infection appears to be driving a substantial component of population-level COVID-19 immunity currently, improved vaccines providing longer lasting (and better sterilizing) immunity are likely to be a critical component of the future pandemic response given the risks associated with SARS-CoV-2 infection.

The health impact of long COVID during the 2021-2022 Omicron wave in Australia: a quantitative burden of disease study

BackgroundLong COVID symptoms occur for a proportion of acute COVID-19 survivors, with reduced risk among the vaccinated, and for Omicron compared to Delta variant infections. The health loss attributed to pre-Omicron long COVID has previously been estimated using only a few major symptoms. MethodsThe years lived with disability (YLDs) due to long COVID in Australia during the 2021-2022 Omicron BA.1/BA.2 wave were calculated using inputs from previously published case-control, cross-sectional, or cohort studies examining the prevalence and duration of individual long COVID symptoms. This estimated health loss was compared with acute SARS-CoV-2 infection YLDs and years of life lost (YLLs) from SARS-CoV-2. The sum of these three components equals COVID-19 disability-adjusted life years (DALYs); this was compared to DALYs from other diseases. Results5200 (95% uncertainty interval [UI] 2200-8300) YLDs were attributable to long COVID and 1800 (95% UI 1100-2600) to acute SARS-CoV-2 infection, suggesting long COVID caused 74% of the overall YLDs from SARS-CoV-2 infections in the BA.1/BA.2 wave. Total DALYs attributable to SARS-CoV-2 were 50 900 (95% UI 21 000-80 900), 2.4% of expected DALYs for all diseases in the same period. ConclusionThis study provides a comprehensive approach to estimating the morbidity due to long COVID. Improved data on long COVID symptoms will improve the accuracy of these estimates. As data accumulates on SARS-CoV-2 infection sequelae (e.g., increased cardiovascular disease rates), total health loss is likely to be higher than estimated in this study. Nevertheless, this study demonstrates that long COVID requires consideration in pandemic policy planning given it is responsible for the majority of direct SARS-CoV-2 morbidity, including during an Omicron wave in a highly vaccinated population. Key messagesO_LIOur study is the first to comprehensively estimate long COVID morbidity using its individual symptoms, during Australias 2021-2022 Omicron wave. C_LIO_LIWe show that long COVID contributed to almost three-quarters of the non-fatal health loss resulting from Omicron infections in this period. C_LIO_LILong COVID contributes to a substantial proportion of direct COVID-19 morbidity, even in a highly vaccinated population during an Omicron wave. It should therefore be more explicitly considered in future pandemic policymaking. C_LIO_LIOur method of estimating long COVID morbidity has explicable differences to existing long COVID burden of disease approaches and may provide a more accurate estimate of the morbidity attributable to long COVID. C_LI

An integrated epidemiologic and economic model to assess optimal COVID-19 pandemic policy

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSIdentifying optimal COVID-19 policies is challenging. For Victoria, Australia (6.6 million people), we evaluated 104 policy packages (two levels of stringency of public health and social measures [PHSMs], by two levels each of mask-wearing and respirator provision during large outbreaks, by 13 vaccination schedules) for nine future SARS-CoV-2 variant scenarios. MethodsWe used an agent-based model to estimate morbidity, mortality, and costs over 12 months from October 2022 for each scenario. The 104 policies (each averaged over the nine future variant scenarios) were ranked based on four evenly weighted criteria: cost-effectiveness from (a) health system only and (b) health system plus GDP perspectives, (c) deaths and (d) days exceeding hospital occupancy thresholds. FindingsMore compared to less stringent PHSMs reduced cumulative infections, hospitalisations and deaths but also increased time in stage [≥]3 PHSMs. Any further vaccination from October 2022 decreased hospitalisations and deaths by 12% and 27% respectively compared to no further vaccination and was usually a cost-saving intervention from a health expenditure plus GDP perspective. High versus low vaccine coverage decreased deaths by 15% and reduced time in stage [≥]3 PHSMs by 20%. The modelled mask policies had modest impacts on morbidity, mortality, and health system pressure. The highest-ranking policy combination was more stringent PHSMs, two further vaccine doses (an Omicron-targeted vaccine followed by a multivalent vaccine) for [≥]30-year-olds with high uptake, and promotion of increased mask wearing (but not Government provision of respirators). InterpretationOngoing vaccination and PHSMs continue to be key components of the COVID-19 pandemic response. Integrated epidemiologic and economic modelling, as exemplified in this paper, can be rapidly updated and used in pandemic decision making. FundingAnonymous donation, University of Melbourne funding. AO_SCPLOWBSTRACTC_SCPLOW BackgroundIdentifying optimal COVID-19 policies is challenging. For Victoria, Australia (6.6 million people), we evaluated 104 policy packages: (a) two levels of stringency of public health and social measures (PHSMs; lower, higher), by (b) two levels each of mask wearing (low, high) and Government respirator provision (nil, yes) during large outbreaks (defined as when the projected number of people in hospital reached >270 or >130 per million population for lower and higher stringency PHSM settings respectively), by (c) 13 vaccination schedules (nil, and four combinations of low/high coverage for [≥]30/60-year-olds, each with an Omicron-targeted (OT) booster in the last quarter of 2022 followed by one of: nil, another OT booster in the second quarter of 2023, or a multivalent booster in the second quarter of 2023). These policies were modelled in the setting of nine future SARS-CoV-2 variant scenarios (no major new variant of concern and one of eight variants arriving in November 2022 with different virulence, antigenic, and immune escape profiles). MethodsWe used an agent-based model to estimate morbidity, mortality, and costs over 12 months from October 2022 for each scenario. The 104 policies (each averaged over the nine future variant scenarios) were ranked based on four evenly weighted criteria: cost-effectiveness from (a) health system only and (b) health system plus GDP perspectives (HALYs valued at AUD 70,000; discount rate 3%), (c) deaths and (d) days exceeding hospital occupancy thresholds. FindingsMore compared to less stringent PHSMs reduced cumulative infections, hospitalisations and deaths by an average of 25%, 24% and 24% respectively across 468 policy comparisons (other policy and variant scenarios held constant), but also increased time in stage [≥]3 (out of 5) PHSMs by an average of 42 days (23 days for low virulence and 70 days for high virulence variants). Any further vaccination from October 2022 decreased hospitalisations and deaths by 12% and 27% respectively compared to no further vaccination, however the cumulative number of infections increased by 10% due to vaccination preferentially decreasing hospitalisation rates that were used to dynamically set PHSM stages. Any further vaccination was of marginal cost-effectiveness from a health system perspective (an average of AUD 77,500 per HALY gained for vaccinating [≥]60-year-olds, and AUD 41,600 for 30- to 59-year-olds incremental to [≥]60-year-olds), but vaccination also resulted in 36% fewer days in Stage [≥]3 PHSMs usually making it a cost-saving intervention from a health expenditure plus GDP perspective. High versus low vaccine coverage reduced deaths by 15% and reduced time in Stage [≥]3 PHSMs by 20%. Promotion to increase mask wearing or government provision of respirators during large outbreaks reduced cumulative infections, hospitalisations and deaths over the 12 months by 1% to 2%, and reduced days with hospital occupancy exceeding 750 COVID-19 patients by 2% (4% to 5% in the context of highly virulent variants). The highest-ranking policy combination was more stringent PHSMs, two further vaccine doses (an Omicron-targeted vaccine followed by a multivalent vaccine) for [≥]30-year-olds with high uptake, and promotion of increased mask wearing (but not Government provision of respirators). InterpretationOngoing vaccination and PHSMs continue to be key components of the COVID-19 pandemic response. Integrated epidemiologic and economic modelling, as exemplified in this paper, can be rapidly updated and used in pandemic decision making. FundingAnonymous donation, University of Melbourne funding. RO_SCPLOWESEARCHC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWINC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWCONTEXTC_SCPLOW Evidence before this studyWe searched Ovid MEDLINE to 28 July 2022 for studies using the terms (economic evaluation.mp. OR cost effectiveness.mp. OR health economic*.mp.) AND (simulation.mp. OR model*.mp.) AND pandemic*.mp. to identify existing simulation modelling analyses of pandemic preparedness and response that incorporated cost effectiveness considerations. All identified literature examined pandemic influenza and COVID-19 and was highly heterogeneous in terms of modelled interventions (which included school closures, masks, hand hygiene, vaccination, testing strategies, antiviral medication, physical distancing measures, indoor ventilation, and personal protective equipment), quality, context, model structure, and economic evaluation approach. Systematic reviews of COVID-19 modelling studies that include a health economic component generally indicate that SARS-CoV-2 testing, personal protective equipment, masks, and physical distancing measures are cost-effective. However, few prior studies consider optimal packages of interventions (as opposed to standalone interventions), and none explicitly account for ongoing viral evolution or accurately capture the complexities of vaccine- or natural infection-derived immunity to SARS-CoV-2. For example, a previous study integrating a dynamic SARS-CoV-2 transmission model with an economic analysis using a net monetary benefit approach published in early 2021 emphasized the combined public health and economic advantages of COVID-19 vaccination combined with physical distancing measures in the UK. However, considering current knowledge regarding the substantial waning of vaccine effectiveness and relatively low protection against infection conferred by vaccination (compared to more severe clinical outcomes), this model likely over-estimated the impact of COVID-19 vaccination on viral transmission. Scenarios that considered the emergence of SARS-CoV-2 variants of concern and thus associated changes in viral transmissibility, immune escape capacity (which has, in the case of the Omicron variant, greatly reduced protection following vaccination and prior infection) or virulence were also not modelled. Added value of this studyTo our knowledge, our study is the first that utilises a dynamic disease transmission model combined with an integrated economic evaluation framework to systematically compare COVID-19 policy intervention packages while accounting for ongoing SARS-CoV-2 evolution and waning population immunity. At a high-level, we found that a considerable degree of COVID-19 disease burden should be expected in the future, with modelled interventions only able to partly mitigate pandemic-associated morbidity and mortality in the medium-term. Across nine plausible future SARS-CoV-2 variant scenarios, higher stringency PHSMs notably reduced cumulative infections, hospitalisations and deaths in the 12-month period modelled but had the tradeoff of higher expected societal economic losses. Increasing community mask-wearing and substituting cloth and surgical masks for government supplied respirators during periods of high SARS-CoV-2 morbidity both reduced the number of days with hospital occupancy exceeding 750 COVID-19 patients by 2% on average across scenarios, and minimally reduced the cumulative infection, hospitalization and death burden. Compared to no further vaccines, the modelled vaccination schedules (with next-generation vaccines; one or two further doses) reduced hospitalisations by an average of 12%, and deaths by 27%. Vaccinating [≥]30-year-olds was modestly superior to just vaccinating [≥]60-year-olds (reducing cumulative deaths, for example, by 3.1%). Considering all policy options together, and ranking by optimality on cost-effectiveness, health system pressure and deaths, the highest ranking policy combinations tended to be a mix of higher stringency PHSMs, promotion to increase mask wearing but no Government-funded respirator provision during large outbreaks, and the administration of two booster vaccine doses within the 12-month period to [≥]30-year-olds with associated high coverage (noting gains from vaccinating [≥]30-year-olds compared to [≥]60-year-olds were modest). Implications of all the available evidenceThe policy implications of this study are three-fold. Firstly, it reinforces the cost-effectiveness of ongoing vaccination of the public to mitigate morbidity and mortality associated with COVID-19. Secondly, the characteristics of emerging SARS-CoV-2 variants, outside the control of policy makers, will likely substantially influence public health outcomes associated with the pandemic in the future. Finally, at a phase of the pandemic characterised by growing intervention options urgently requiring prioritisation by decision makers alongside a large degree of ongoing uncertainty about future variants, this study provides a framework within which to systematically compare the health and economic benefits and burdens of packages of interventions that can be rapidly updated with new information (such as estimated effectiveness and waning kinetics of newly-developed vaccines) to support policy making.

A log-odds system for waning and boosting of COVID-19 vaccine effectiveness

Immunity to SARS-CoV-2 following vaccination wanes over time in a non-linear fashion, making modelling of likely population impacts of COVID-19 policy options challenging. We observed that it was possible to mathematize non-linear waning of vaccine effectiveness (VE) on the percentage scale as linear waning on the log-odds scale, and developed a random effects logistic regression equation based on UK Health Security Agency data to model VE against Omicron following two and three doses of a COVID-19 vaccine. VE on the odds scale reduced by 47% per month for symptomatic infection after two vaccine doses, lessening to 35% per month for hospitalisation. Waning on the odds scale after triple dose vaccines was 35% per month for symptomatic disease and 19% for hospitalisation. This log-odds system for estimating waning and boosting of COVID-19 VE provides a simple solution that may be used to parametrize SARS-CoV-2 immunity over time parsimoniously in epidemiological models.