Cost-effective boosting allocations in the post-Omicron era of COVID-19 management (preprint)

BackgroundFollowing widespread exposure to Omicron variants, COVID-19 has transitioned to endemic circulation. Populations now have diverse infection and vaccination histories, resulting in heterogeneous immune landscapes. Careful consideration of vaccination is required through the post-Omicron phase of COVID-19 management to minimise disease burden. We assess the impact and cost-effectiveness of targeted COVID-19 vaccination strategies to support global vaccination recommendations. MethodsWe integrated immunological, transmission, clinical and cost-effectiveness models, and simulated populations with different characteristics and immune landscapes. We calculated the expected number of infections, hospitalisations and deaths for different vaccine scenarios. Costs (from a healthcare perspective) were estimated for exemplar country income level groupings in the Western Pacific Region. Results are reported as incremental costs and disability-adjusted life years averted compared to no additional vaccination. Parameter and stochastic uncertainty were captured through scenario and sensitivity analysis. FindingsAcross different population demographics and income levels, we consistently found that annual elder-targeted boosting strategies are most likely to be cost-effective or cost-saving, while paediatric programs are unlikely to be cost-effective. Results remained consistent while accounting for uncertainties in the epidemiological and economic models. Half-yearly boosting may only be cost-effective in higher income settings with older population demographics and higher cost-effectiveness thresholds. InterpretationThe seresults demonstrate the value of continued booster vaccinations to protect against severe COVID-19 disease outcomes across high and middle-income settings and show that the biggest health gains relative to vaccine costs are achieved by targeting older age-groups. FundingFunded by the World Health Organization. O_TEXTBOXResearch in context Evidence before this studyWith COVID-19 now globally endemic, populations exhibit varying levels of natural and vaccine-acquired immunity to SARS-CoV-2. With widespread, if variable, immunity resulting in reduced severity of COVID-19 disease, re-evaluation of the ongoing value of vaccination is required. COVID-19 vaccination strategies must consider the cost-effectiveness of gains from vaccination given prior immunity, and in the context of income and health system capacity to manage COVID-19 alongside other pressing concerns. Few articles examine cost-effectiveness of COVID-19 vaccination strategies in populations with diverse characteristics and waning hybrid immunity, though there is a large body of literature that considers some combination of these elements or focus on one particular country. Consensus is that allocating vaccine doses to older age groups and those at higher risk of severe disease is most beneficial, albeit assuming either only past natural immunity or no waning immunity. These studies have either not included a cost-effectiveness analysis or, where present, have typically assumed a base case zero-vaccination scenario. Added value of this studyWe consider the contemporary situation where populations have varying degrees of hybrid immunity resulting from both prior infection and vaccination, and where the relevant cost-effectiveness analysis considers only future primary and booster doses in the population. We describe multiple demographics, using exemplar older and younger populations, in conjunction with low to high past vaccination coverage, low to high past natural infection incidence, and low to high income levels. Under these settings, we determine the cost-effectiveness of a range of targeted boosting strategies (who, when, what). Implications of all the available evidenceOur study highlights how future COVID-19 booster doses targeted towards older age groups at risk of severe outcomes can be cost-effective or cost-saving in high-income settings with populations that have a higher proportion of individuals at risk. In younger, lower-resourced settings, annual boosting of older age groups may still be cost-effective or cost-saving in some scenarios. We consistently find that pediatric vaccination is not cost-effective. Given the benefits of vaccination, especially to reduce severe disease, we show the importance of ongoing global efforts to provide and equitably distribute vaccines and strengthen adult immunisation programs. C_TEXTBOX

Cohort Profile: A longitudinal Victorian COVID-19 cohort (COVID PROFILE) (preprint)

Purpose: The COVID PROFILE cohort is a longitudinal clinical study based in Victoria Australia, which was established to understand immunity to SARS-CoV-2 in a low transmission population setting and to identify immunological markers of long-term immunity and immune-dysregulation after both infection and vaccination. Additionally, this cohort was established as a biobank resource for researchers to address other health-related immunological questions. Participants: We enrolled 178 adult community members, including household contacts, who had either recovered from a SARS-CoV-2 infection or were SARS-CoV-2 naive. Only participants 18 years of age or older and, in the case of female participants, non-pregnant women at the time of enrollment were included in the study. Detailed COVID-19 clinical data, vaccination status, medical history and demographics was collected. Findings to date: At enrollment, we found that 87.8% of COVID-19 recovered individuals were seropositive with detectable levels of anti-SARS-CoV-2 IgG antibodies. Seronegative COVID-19 recovered individuals included asymptomatic individuals or participants that were enrolled more than 12 months after their COVID-19 diagnosis. Except for one individual who was seropositive at baseline despite a previous SARS-CoV-2 PCR negative diagnosis, all household contacts and other community members enrolled as SARS-CoV-2 PCR negative, were seronegative for all SARS-CoV-2-specific antibodies tested. The infection rate (re-infection or new infection) during 24 months of the study was 42.7%, as determined by either rapid antigen tests, PCRs or serology screens. Of the SARS-CoV-2 recovered participants, 32.6% reported ongoing symptoms at enrollment of which 47% had already experienced ongoing symptoms for more than 12 weeks. Future Plans: COVID PROFILE will be used to comprehensively understand temporal immunity to SARS-CoV-2 and COVID-19 vaccines and to understand the impact of host immunological composition on such immunity and symptom severity. Additionally, studies focusing on understanding immunity following breakthrough infections and immunological risk factors that contribute towards development of long COVID are planned.

Modelling the impact of hybrid immunity on future COVID-19 epidemic waves (preprint)

Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization (WHO) Western Pacific Region (WPR). We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.

Identification of novelPlasmodium vivaxproteins associated with protection against clinical malaria (preprint)

As progress towards malaria elimination continues, the challenge posed by the parasite species Plasmodium vivax has become more evident. In many regions co-endemic for P. vivax and Plasmodium falciparum , as transmission has declined the proportion of cases due to P. vivax has increased. Novel tools that directly target P. vivax are thus warranted for accelerated elimination. There is currently no advanced vaccine for P. vivax and only a limited number of potential candidates in the pipeline. In this study we aimed to identify promising P. vivax proteins that could be used as part of a subunit vaccination approach. We screened 342 P. vivax protein constructs for their ability to induce IgG antibody responses associated with protection from clinical disease in a cohort of children from Papua New Guinea. This approach has previously been used to successfully identify novel candidates. We were able to confirm previous results from our laboratory identifying the proteins reticulocyte binding protein 2b and StAR-related lipid transfer protein, as well as at least four novel candidates with similar levels of predicted protective efficacy. Assessment of these P. vivax proteins in further studies to confirm their potential and identify functional mechanisms of protection against clinical disease are warranted.

Serological reconstruction of COVID-19 epidemics through analysis of antibody kinetics to SARS-CoV-2 proteins (preprint)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. Waning antibody levels lead to reduced sensitivity of serological diagnostic tests over time. This undermines the utility of serological surveillance as the SARS-CoV-2 pandemic progresses into its second year. Here we develop a multiplex serological test for measuring antibodies of three isotypes (IgG, IgM, IgA) to five SARS-CoV-2 antigens (Spike (S), receptor binding domain (RBD), Nucleocapsid (N), Spike subunit 2, Membrane-Envelope fusion) and the Spike proteins of four seasonal coronaviruses. We measure antibody responses in several cohorts of French and Irish hospitalized patients and healthcare workers followed for up to eleven months after symptom onset. The data are analysed with a mathematical model of antibody kinetics to quantify the duration of antibody responses accounting for inter-individual variation. One year after symptoms, we estimate that 36% (95% range: 11%, 94%) of anti-S IgG remains, 31% (9%, 89%) anti-RBD IgG remains, and 7% (1%, 31%) anti-N IgG remains. Antibodies of the IgM isotype waned more rapidly, with 9% (2%, 32%) anti-RBD IgM remaining after one year. Antibodies of the IgA isotype also waned rapidly, with 10% (3%, 38%) anti-RBD IgA remaining after one year. Quantitative measurements of antibody responses were used to train machine learning algorithms for classification of previous infection and estimation of time since infection. The resulting diagnostic test classified previous infections with 99% specificity and 98% (95% confidence interval: 94%, 99%) sensitivity, with no evidence for declining sensitivity over the time scale considered. The diagnostic test also provided accurate classification of time since infection into intervals of 0 - 3 months, 3 - 6 months, and 6 - 12 months. Finally, we present a computational method for serological reconstruction of past SARS-CoV-2 transmission using the data from this test when applied to samples from a single cross-sectional sero-prevalence survey.

INFERRED RESOLUTION THROUGH HERD IMMMUNITY OF FIRST COVID-19 WAVE IN MANAUS, BRAZILIAN AMAZON (preprint)

As in many other settings, peak excess mortality preceded the officially reported `first wave' peak of the COVID-19 epidemic in Manaus, Brazil, reflecting delayed case recognition and limited initial access to diagnostic testing. To avoid early information bias, we used detailed age and gender stratified death certificate and hospitalisation data to evaluate the epidemic's trajectory and infer the cause of its decline using a stochastic model. Our results are consistent with heterogenous transmission reducing over time due to the development of herd immunity. Relative to a baseline model that assumed homogenous mixing across Manaus, a model that permitted a small, self-isolated population fraction raised the estimated herd-immunity threshold from 28% to 30% and reduced the final attack rate from 86% to 65%. In the latter scenario, a substantial proportion of vulnerable, older individuals remained susceptible to infection. Given uncertainties regarding the distancing behaviours of population subgroups with different social and economic characteristics, and the duration of sterilising or transmission-modifying immunity in exposed individuals, we conclude that the potential for epidemic outbreaks remains, but that future waves of infection are likely to be much less pronounced than that already experienced.

A comparison of non-magnetic and magnetic beads for measuring IgG antibodies against P. vivax antigens in a multiplexed bead-based assay using Luminex® technology (Bio-Plex® 200 or MAGPIX®) (preprint)

Multiplexed bead-based assays that use Luminex xMAP ® technology have become popular for measuring antibodies against proteins of interest in many fields, including malaria and more recently SARS-CoV-2/COVID-19. There are currently two formats that are widely used: non-magnetic beads or magnetic beads. Data is lacking regarding the comparability of results obtained using these two types of beads, and for assays run on different instruments. Whilst non-magnetic beads can only be run on flow-based instruments (such as the Luminex ® 100/200™ or Bio-Plex ® 200), magnetic beads can be run on both these and the newer MAGPIX ® instruments. In this study we utilized a panel of purified recombinant Plasmodium vivax proteins and samples from malaria-endemic areas to measure P. vivax -specific IgG responses using different combinations of beads and instruments. We directly compared: i) non-magnetic versus magnetic beads run on a Bio-Plex ® 200, ii) magnetic beads run on the Bio-Plex ® 200 versus MAGPIX ® and iii) non-magnetic beads run on a Bio-Plex ® 200 versus magnetic beads run on the MAGPIX ® . We also performed an external validation of our optimized assay. We observed that IgG antibody responses, measured against our panel of P. vivax proteins, were strongly correlated in all three of our comparisons, however higher amounts of protein were required for coupling to magnetic beads. Our external validation indicated that results generated in different laboratories using the same coupled beads are also highly comparable, particularly if a reference standard curve is used.

Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics (preprint)

Background Infection with SARS-CoV-2 induces an antibody response targeting multiple antigens that changes over time. This complexity presents challenges and opportunities for serological diagnostics. Methods A multiplex serological assay was developed to measure IgG and IgM antibody responses to seven SARS-CoV-2 spike or nucleoprotein antigens, two antigens for the nucleoproteins of the 229E and NL63 seasonal coronaviruses, and three non-coronavirus antigens. Antibodies were measured in serum samples from patients in French hospitals with RT-qPCR confirmed SARS-CoV-2 infection (n = 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic (n = 335). A random forests algorithm was trained with the multiplex data to classify individuals with previous SARS-CoV-2 infection. A mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the potential sensitivity and classification performance of serological diagnostics during the first year following symptom onset. A statistical estimator is presented that can provide estimates of seroprevalence in very low transmission settings. Results IgG antibody responses to trimeric Spike protein identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 91.6% sensitivity (95% confidence interval (CI); 87.5%, 94.5%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG and IgM to multiple antigens, it was possible to identify infected individuals with 98.8% sensitivity (95% CI; 96.5%, 99.6%) and 99.3% specificity (95% CI; 97.6%, 99.8%). Informed by prior data from other coronaviruses, we estimate that one year following infection a monoplex assay with optimal anti-Stri IgG cutoff has 88.7% sensitivity (95% CI: 63.4%, 97.4%), and that a multiplex assay can increase sensitivity to 96.4% (95% CI: 80.9%, 100.0%). When applied to population-level serological surveys, statistical analysis of multiplex data allows estimation of seroprevalence levels less than 1%, below the false positivity rate of many other assays. Conclusion Serological signatures based on antibody responses to multiple antigens can provide accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. This provides potential solutions to two pressing challenges for SARS-CoV-2 serological surveillance: classifying individuals who were infected greater than six months ago, and measuring seroprevalence in serological surveys in very low transmission settings.