Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 39 Records) |
Query Trace: Lipsitch M[original query] |
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Reduced effectiveness of repeat influenza vaccination: distinguishing among within-season waning, recent clinical infection, and subclinical infection
Bi Q , Dickerman BA , Nguyen HQ , Martin ET , Gaglani M , Wernli KJ , Balasubramani GK , Flannery B , Lipsitch M , Cobey S . J Infect Dis 2024 Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A(H3N2) (OR=1.11, 95%CI:1.02-1.21) but not for influenza B or A(H1N1). We found that clinical infection influenced individuals' decision to vaccinate in the following season while protecting against clinical infection of the same (sub)type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on VE. |
JYNNEOS™ effectiveness as post-exposure prophylaxis against Mpox: Challenges using real-world outbreak data
Rosen JB , Arciuolo RJ , Pathela P , Boyer CB , Baumgartner J , Latash J , Malec L , Lee EH , Reddy V , King R , Edward Real J , Lipsitch M , Zucker JR . Vaccine 2024 BACKGROUND: JYNNEOS(TM) vaccine has been used as post-exposure prophylaxis (PEP) during a mpox outbreak in New York City (NYC). Data on effectiveness are limited. METHODS: Effectiveness of a single dose of JYNNEOS(TM) vaccine administered subcutaneously ≤ 14 days as PEP for preventing mpox disease was assessed among individuals exposed to case-patients from May 22, 2022-August 24, 2022. Individuals were evaluated for mpox through 21 days post-exposure. An observational study was conducted emulating a sequence of nested "target" randomized trials starting each day after exposure. Results were adjusted for exposure risk and race/ethnicity. Analyses were conducted separately based on last (PEP(L)) and first (PEP(F)) exposure date. We evaluated the potential to overestimate PEP effectiveness when using conventional analytic methods due to exposed individuals developing illness before they can obtain PEP (immortal time bias) compared to the target trial. RESULTS: Median time from last exposure to symptom onset (incubation period) among cases that did not receive PEP(L) was 7 days (range 1-16). Time to PEP(L) receipt was 7 days (range 0-14). Among 549 individuals, adjusted PEP(L) and PEP(F) effectiveness was 19 % (95 % Confidence Interval [CI], -54 % to 57 %) and -7% (95 % CI, -144 % to 53 %) using the target trial emulation, respectively, and 78 % (95 % CI, 50 % to 91 %) and 73 % (95 % CI, 31 % to 91 %) using conventional analysis. CONCLUSIONS: Determining PEP effectiveness using real-world data during an outbreak is challenging. Time to PEP in NYC coupled with the observed incubation period resulted in overestimated PEP effectiveness using a conventional method. The target trial emulation, while yielding wide confidence intervals due to small sample size, avoided immortal time bias. While results from these evaluations cannot be used as reliable estimates of PEP effectiveness, we present important methodologic considerations for future evaluations. |
What's next: using infectious disease mathematical modelling to address health disparities
Richard DM , Lipsitch M . Int J Epidemiol 2023 Before and during the COVID-19 pandemic, an individual’s age and race/ethnicity have been highly predictive of their risk of infectious diseases and their health consequences. Disparities were evidenced in COVID-19 incidence rates and in hospitalization, severity and mortality metrics in the USA1 and in other countries.2,3 Identifying these disparate outcomes associated with demographic variables is valuable mainly if it prompts investigation into what mechanisms generate the disparities and inform how they can be reduced.4 A prominent report from the UK succinctly outlined that social determinants such as occupation, household characteristics, surrounding population density, urbanicity and social deprivation were all associated with increased risk of COVID-19 infection.3 Others have noted that social determinants can play a role in all stages of an outbreak, providing pathways for unequal exposure, transmission, susceptibility and treatment that produce and escalate disparities in health outcomes.5 |
Examining bias from differential depletion of susceptibles in vaccine effectiveness estimates in settings of waning
Kahn R , Feikin DR , Wiegand RE , Lipsitch M . Am J Epidemiol 2023 193 (1) 232-234 Waning of the effectiveness of COVID-19 vaccines against SARS-CoV-2 infection and | symptomatic disease has been observed in many settings (1-3). The documented ability of | booster doses to restore vaccine effectiveness (VE) to higher levels suggests at least some of | the observed waning is real (3-4). However, differential depletion of susceptibles through | infection-induced immunity related to individuals’ vaccination status can create bias that induces | spurious waning, complicating interpretation of vaccine effectiveness estimates (5-8). | In previous work (5), we showed that spurious waning was detectable but modest in settings | without true waning where true VE was very high (0.95) and constant over time (i.e., no true | waning), and more notable in settings where true VE was lower (0.70) and constant over time. | This led us to the natural question: Is spurious waning modest or more notable in situations | where true effectiveness wanes over time? Here we examine bias that can arise in settings in | which true waning occurs. |
Identifying and alleviating bias due to differential depletion of susceptible people in post-marketing evaluations of COVID-19 vaccines (preprint)
Kahn R , Schrag SJ , Verani JR , Lipsitch M . medRxiv 2021 2021.07.15.21260595 Recent studies have provided key information about SARS-CoV-2 vaccines’ efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptibles between vaccinated and unvaccinated groups. Here we examine the extent to which biases occur under different scenarios and assess whether serologic testing has the potential to correct this bias. By identifying non-vaccine antibodies, these tests could identify individuals with prior infection. We find in scenarios with high baseline VE, differential depletion of susceptibles creates minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE is lower, the bias for leaky vaccines (that reduce individual probability of infection given contact) is larger and should be corrected by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serologic testing, on this critical variable.Competing Interest StatementDr. Lipsitch reports consulting/honoraria from Bristol Myers Squibb, Sanofi Pasteur, and Merck, as well as a grant through his institution, unrelated to COVID-19, from Pfizer. He has served as an unpaid advisor related to COVID-19 to Pfizer, One Day Sooner, Astra-Zeneca, Janssen, and COVAX (United Biomedical). Dr. Kahn discloses consulting fees from Partners In Health.Funding StatementThis work was supported by the U.S. National Cancer Institute Seronet cooperative agreement U01CA261277. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesCode is available on github. https://github.com/rek160/spurious-waning |
Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial – BCPP/ Ya Tsie trial (preprint)
Magosi LE , Zhang Y , Golubchik T , DeGruttola V , Tchetgen Tchetgen E , Novitsky V , Moore J , Bachanas P , Segolodi T , Lebelonyane R , Pretorius Holme M , Moyo S , Makhema J , Lockman S , Fraser C , Essex MM , Lipsitch M . medRxiv 2021 2021.06.19.21259186 Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] versus 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] versus 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The trial was approved by the Botswana Health Research and Development Committee, the institutional review board of the Centers for Disease Control and Prevention and the Harvard School of Public Health Office of Regulatory Affairs and Research Compliance; and was monitored by a data and safety monitoring board and Westat. Written informed consent for enrollment in the trial and viral HIV genotyping was obtained from all participants.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are within the paper and the Supplemental Notes, figures and tables. HIV-1 reads are available on reasonable request through the PANGEA consortium (www.pangea-hiv.org) |
Nowcasting by Bayesian Smoothing: A flexible, generalizable model for real-time epidemic tracking (preprint)
McGough SF , Johansson MA , Lipsitch M , Menzies NA . bioRxiv 2019 663823 Delays in case reporting are common to disease surveillance systems, making it difficult to track diseases in real-time. “Nowcast” approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission—that future cases are intrinsically linked to past reported cases—and are optimized to a single application, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting package. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package “NobBS”) for widespread application.Significance Achieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. However, approaches that seek to estimate cases in spite of reporting delays often do not consider the temporal relationship between cases during an outbreak, nor do they identify characteristics of robust approaches that generalize to a wide range of surveillance contexts with very different reporting delays. Here, we present a smooth Bayesian nowcasting approach that produces accurate estimates that capture the time evolution of the epidemic curve and outperform a previous approach in the literature. We assess the performance for two diseases to identify important features of the reporting delay distribution that contribute to the model’s performance and robustness across surveillance settings. |
Hospitalizations associated with respiratory syncytial virus (RSV) and influenza in children, including children having a diagnosis of asthma (preprint)
Goldstein E , Finelli L , O'Halloran A , Liu P , Karaca Z , Steiner CA , Viboud C , Lipsitch M . bioRxiv 2019 161067 Background There is uncertainty about the burden of hospitalization associated with RSV and influenza in children, including those with underlying medical conditions.Methods We applied previously developed methodology (Goldstein et al., Epidemiology 2012) to HealthCare Cost and Utilization Project (HCUP) hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003-2010.Results The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2381 (95% CI(2252,2515)) in age <1y; 710.6(609.1,809.2) (age 1y); 395(327.7,462.4) (age 2y); 211.3(154.6,266.8) (age 3y); 111.1(62.4,160.1) (age 4y); 72.3(29.3,116.4) (ages 5-6y); 35.6(9.9,62.2) (ages 7-11y); and 39(17.5,60.6) (ages 12-17y).The corresponding rates of influenza-associated hospitalization were lower, ranging from 181(142.5,220.3) in age <1y to 17.9(11.7,24.2) in ages 12-17y. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups under 5y ranged between 3.1(2.1,4.7) (age <1y) to 6.7(4.2,11.8) (age 2y); the corresponding risks for influenza-related hospitalization ranged from 2.8(2.1,4) (age <1y) to 4.9(3.8,6.4) (age 3y).Conclusions RSV-associated hospitalization rates in young children are high and decline rapidly with age. Young children with an asthma diagnosis should be target groups for RSV and influenza-related mitigation efforts, possibly including RSV prophylaxis for the youngest children. |
Evaluating reduced effectiveness after repeat influenza vaccination while accounting for confounding by recent infection and within-season waning (preprint)
Bi Q , Dickerman BA , McLean HQ , Martin ET , Gaglani M , Wernli KJ , Goundappa B , Flannery B , Lipsitch M , Cobey S , Murthy K , Raiyani C , Dunnigan K , Mamawala M , Chung JR , Patel M , Lamerato L , Jackson ML , Phillips CH , Kiniry E , Belongia EA , King JP , Monto AS , Zimmerman RK , Nowalk MP , Geffel KM . medRxiv 2023 17 Background. Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees in a given season. Understanding the underlying causes requires consideration of within-season waning and recent infection. Methods. Using the US Flu Vaccine Effectiveness (VE) Network data over 8 influenza seasons (2011-2012 to 2018-2019), we estimated the effect of prior-season vaccination on the odds of clinical infection in a given season, after accounting for waning vaccine protection using regression methods. We adjusted for potential confounding by recent clinical infection using inverse-probability weighting. We investigated theoretically whether unmeasured subclinical infection in the prior season, which is more likely in the non-repeat vaccinees, could explain the repeat vaccination effect. Results. Repeat vaccinees vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for influenza A(H3N2) (OR=1.11, 95% CI:1.02-1.21) but not for influenza B (OR=1.03, 95% CI:0.89-1.18) or A(H1N1) (OR=1.03, 95% CI:0.90-1.19) compared to those vaccinated in the given season only. Recent clinical infection with the homologous (sub)type protected against clinical infection with A(H3N2) or B. Individuals with clinical infection in one season had 1.11 (95% CI:1.03-1.19) times the odds of switching vaccination status in the following season. Adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. Adjusting for subclinical infection could theoretically attenuate this effect. Conclusion. Waning protection and recent clinical infection were insufficient to explain observed reduced VE in repeat vaccinees with a test-negative design. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. |
Increased vaccine sensitivity of an emerging SARS-CoV-2 variant (preprint)
Lewnard JA , Hong V , Kim JS , Shaw SF , Lewin B , Takhar H , Lipsitch M , Tartof SY . medRxiv 2023 16 (1) 3854 Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with improvements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and >=5 COVID-19 vaccine doses were 10% (95% confidence interval: 1-18%), 11% (3-19%), 13% (3-21%), and 25% (15-34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30-87%] and 48% [7-71%], respectively, for recipients of >=4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11-24%) and 40% (19-65%) higher adjusted odds of having experienced 1 and >=2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. |
Increased vaccine sensitivity of an emerging SARS-CoV-2 variant
Lewnard JA , Hong V , Kim JS , Shaw SF , Lewin B , Takhar H , Lipsitch M , Tartof SY . Nat Commun 2023 14 (1) 3854 Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with enhancements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and ≥5 COVID-19 vaccine doses were 10% (95% confidence interval: 1-18%), 11% (3-19%), 13% (3-21%), and 25% (15-34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater point estimates of protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30-87%] and 48% [7-71%], respectively, for recipients of ≥4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11-24%) and 40% (19-65%) higher adjusted odds of having experienced 1 and ≥2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses. |
Estimated preventable COVID-19-associated deaths due to non-vaccination in the United States
Jia KM , Hanage WP , Lipsitch M , Johnson AG , Amin AB , Ali AR , Scobie HM , Swerdlow DL . Eur J Epidemiol 2023 1-4 While some studies have previously estimated lives saved by COVID-19 vaccination, we estimate how many deaths could have been averted by vaccination in the US but were not because of a failure to vaccinate. We used a simple method based on a nationally representative dataset to estimate the preventable deaths among unvaccinated individuals in the US from May 30, 2021 to September 3, 2022 adjusted for the effects of age and time. We estimated that at least 232,000 deaths could have been prevented among unvaccinated adults during the 15 months had they been vaccinated with at least a primary series. While uncertainties exist regarding the exact number of preventable deaths and more granular data are needed on other factors causing differences in death rates between the vaccinated and unvaccinated groups to inform these estimates, this method is a rapid assessment on vaccine-preventable deaths due to SARS-CoV-2 that has crucial public health implications. The same rapid method can be used for future public health emergencies. |
Learning From COVID-19 to Improve Surveillance for Emerging Threats.
Jernigan DB , George D , Lipsitch M . Am J Public Health 2023 113 (5) e1-e3 As the SARS-CoV-2 virus (the causative agent of COVID-19) began rapidly spreading around the globe in the spring of 2020, existing surveillance systems were not robust or comprehensive enough to meet the tremendous need for real-time, representative characterization of both pathogen and disease. Confronted with these challenges in England, as described by Elliott et al. in this issue of AJPH (p. 545), an alternative, novel, and broadly applicable surveillance platform was established—the Real-time Assessment of Community Transmission-1 (REACT-1) study. This system was designed and purpose-built through a collaboration of public health officials, health care providers, academic modelers, mathematicians, statisticians, logisticians, and epidemiologists. The methods and execution of REACT-1 proved successful in maintaining situational awareness as reported in more than 15 publications and numerous public health reports, leading to meaningful policies and mitigations with significant positive public health impact. Several design and methodological factors contributed to REACT-1’s success and serve as examples for improving surveillance going forward. |
Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment - California, December 2021-May 2022.
Malden DE , Hong V , Lewin BJ , Ackerson BK , Lipsitch M , Lewnard JA , Tartof SY . MMWR Morb Mortal Wkly Rep 2022 71 (25) 830-833 Nirmatrelvir/ritonavir (Paxlovid) is a combination protease inhibitor that blocks replication of SARS-CoV-2 (the virus that causes COVID-19) and has been shown to reduce the risk for hospitalization and death among patients with mild to moderate COVID-19 who are at risk for progression to severe disease* (1). In December 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for early treatment with Paxlovid among persons with mild to moderate cases of COVID-19 who are at high risk for progression to severe disease (2). FDA and a small number of published case reports have documented recurrence of COVID-19 symptoms or a positive viral test result (COVID-19 rebound) 2-8 days after recovery or a negative SARS-CoV-2 test result among patients treated with Paxlovid (3-7); however, large-scale studies investigating severe illness after Paxlovid treatment are limited. This study used electronic health record (EHR) data from a large integrated health care system in California (Kaiser Permanente Southern California [KPSC]) to describe hospital admissions and emergency department (ED) encounters related to SARS-CoV-2 infections during the 5-15 days after pharmacy dispensation of a 5-day treatment course of Paxlovid. Among 5,287 persons aged ≥12 years who received Paxlovid during December 31, 2021-May 26, 2022, 73% had received ≥3 doses of COVID-19 vaccine(†), and 8% were unvaccinated. During the 5-15 days after Paxlovid treatment was dispensed, six hospitalizations and 39 ED encounters considered to be related to SARS-CoV-2 infection were identified, representing <1% of all patients to whom Paxlovid treatment was dispensed during the study period. Among these 45 persons, 21 (47%) were aged ≥65 years, and 35 (78%) had at least one underlying medical condition(§) (8). This study found that hospitalization or ED encounters for COVID-19 during the 5-15 days after Paxlovid treatment was dispensed for mild to moderate COVID-19 illness were rarely identified. When administered as an early-stage treatment, Paxlovid might prevent COVID-19-related hospitalization among persons with mild to moderate cases of COVID-19 who are at risk for progression to severe disease. |
Clinical outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in southern California.
Lewnard JA , Hong VX , Patel MM , Kahn R , Lipsitch M , Tartof SY . Nat Med 2022 28 (9) 1933-1943 Epidemiologic surveillance has revealed decoupling of COVID-19 hospitalizations and deaths from case counts following emergence of the Omicron (B.1.1.529) SARS-CoV-2 variant globally. However, assessment of the relative severity of Omicron variant infections presents challenges because of differential acquired immune protection against Omicron and prior variants, and because longer-term changes have occurred in testing and healthcare practices. Here we show that Omicron variant infections were associated with substantially reduced risk of progression to severe clinical outcomes relative to time-matched Delta (B.1.617.2) variant infections within a large, integrated healthcare system in southern California. Adjusted hazard ratios (aHRs) for any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation, and death comparing cases with Omicron versus Delta variant infection were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72), and 0.21 (0.10-0.44) respectively. This reduced severity could not be explained by differential history of prior infection among cases with Omicron or Delta variant infection, and was starkest among cases not previously vaccinated against COVID-19 (aHR=0.40 [0.33-0.49] for any hospital admission and 0.14 [0.07-0.28] for death). Infections with the Omicron BA.2 subvariant were not associated with differential risk of severe outcomes in comparison to BA.1/BA.1.1 subvariant infections. Lower risk of severe clinical outcomes among cases with Omicron variant infection should inform public health response amid establishment of the Omicron variant as the dominant SARS-CoV-2 lineage globally. |
Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial - BCPP/ Ya Tsie trial.
Magosi LE , Zhang Y , Golubchik T , DeGruttola V , TchetgenTchetgen E , Novitsky V , Moore J , Bachanas P , Segolodi T , Lebelonyane R , PretoriusHolme M , Moyo S , Makhema J , Lockman S , Fraser C , Essex MM , Lipsitch M . Elife 2022 11 Background: Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. Methods: To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV-intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana. We sequenced HIV viral whole genomes from 5,114 trial participants among the 30 trial communities. Results: Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] versus 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] versus 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention. Conclusion: Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies. Funding: This study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911). |
Identifying and alleviating bias due to differential depletion of susceptible people in post-marketing evaluations of COVID-19 vaccines.
Kahn R , Schrag SJ , Verani JR , Lipsitch M . Am J Epidemiol 2022 191 (5) 800-811 Recent studies have provided key information about SARS-CoV-2 vaccines' efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptibles between vaccinated and unvaccinated groups. Here we examine the extent to which biases occur under different scenarios and assess whether serologic testing has the potential to correct this bias. By identifying non-vaccine antibodies, these tests could identify individuals with prior infection. We find in scenarios with high baseline VE, differential depletion of susceptibles creates minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE is lower, the bias for leaky vaccines (that reduce individual probability of infection given contact) is larger and should be corrected by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serologic testing, on this critical variable. |
Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.
Patel MK , Bergeri I , Bresee JS , Cowling BJ , Crowcroft NS , Fahmy K , Hirve S , Kang G , Katz MA , Lanata CF , L'Azou Jackson M , Joshi S , Lipsitch M , Mwenda JM , Nogareda F , Orenstein WA , Ortiz JR , Pebody R , Schrag SJ , Smith PG , Srikantiah P , Subissi L , Valenciano M , Vaughn DW , Verani JR , Wilder-Smith A , Feikin DR . Vaccine 2021 39 (30) 4013-4024 Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results. |
Leveraging vaccines to reduce antibiotic use and prevent antimicrobial resistance: a WHO Action Framework
Vekemans J , Hasso-Agopsowicz M , Kang G , Hausdorff WP , Fiore A , Tayler E , Klemm EJ , Laxminarayan R , Srikantiah P , Friede M , Lipsitch M . Clin Infect Dis 2021 73 (4) e1011-e1017 The growing burden of antimicrobial-resistant (AMR) microbes constitutes a significant global threat. Vaccines are effective tools to prevent infections could help to control and prevent AMR. In this Viewpoint we present an Action Framework for vaccines to contribute fully, sustainably and equitably to the prevention and control of AMR by preventing infections and reducing antimicrobial use. The document identifies a series of priority actions in three areas: expanding the use of licensed vaccines to maximize impact on AMR, developing new vaccines that contribute to the prevention and control of AMR, and expanding and sharing knowledge about the impact of vaccines on AMR. The objective of this document is to support an alignment of activities among international vaccine and AMR partners, and structure and articulate key priority actions. |
Nowcasting by Bayesian smoothing: A flexible, generalizable model for real-time epidemic tracking
McGough SF , Johansson MA , Lipsitch M , Menzies NA . PLoS Comput Biol 2020 16 (4) e1007735 Achieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. "Nowcast" approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission-that future cases are intrinsically linked to past reported cases-and are optimized to one or two applications, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting software package while investigating the features of each approach that contribute to good or poor performance. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package "NobBS") for widespread application and provide practical guidance on implementation. |
Hospitalizations associated with respiratory syncytial virus and influenza in children, including children diagnosed with asthma
Goldstein E , Finelli L , O'Halloran A , Liu P , Karaca Z , Steiner CA , Viboud C , Lipsitch M . Epidemiology 2019 30 (6) 918-926 BACKGROUND: There is uncertainty about the burden of hospitalization associated with respiratory syncytial virus (RSV) and influenza in children, including those with underlying medical conditions. METHODS: We applied previously developed methodology to Health Care Cost and Utilization Project hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003 and 2010. RESULTS: The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2,381 (95% CI(2252,2515)) in children <1 year of age; 710.6 (609.1, 809.2) (1 y old); 395 (327.7, 462.4) (2 y old); 211.3 (154.6, 266.8) (3 y old); 111.1 (62.4, 160.1) (4 y old); 72.3 (29.3, 116.4) (5-6 y of age); 35.6 (9.9,62.2) (7-11 y of age); and 39 (17.5, 60.6) (12-17 y of age). The corresponding rates of influenza-associated hospitalization were lower, ranging from 181 (142.5, 220.3) in <1 year old to 17.9 (11.7, 24.2) in 12-17 years of age. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups <5 y ranged between 3.1 (2.1, 4.7) (<1 y old) and 6.7 (4.2, 11.8) (2 y old; the corresponding risks for influenza-related hospitalization ranged from 2.8 (2.1, 4) (<1y old) to 4.9 (3.8, 6.4) (3 y old). CONCLUSION: RSV-associated hospitalization rates in young children are high and decline rapidly with age. There are additional risks for both RSV and influenza hospitalization associated with a prior diagnosis of asthma, with the rates of RSV-related hospitalization in the youngest children diagnosed with asthma being particularly high. |
Azithromycin susceptibility among Neisseria gonorrhoeae isolates and seasonal macrolide use
Olesen SW , Torrone EA , Papp JR , Kirkcaldy RD , Lipsitch M , Grad YH . J Infect Dis 2019 219 (4) 619-623 Rising azithromycin nonsusceptibility among Neisseria gonorrhoeae isolates threatens current treatment recommendations, but the cause of this rise is not well understood. We performed an ecological study of seasonal patterns in macrolide use and azithromycin resistance in N. gonorrhoeae, finding that population-wide macrolide use is associated with increased azithromycin nonsusceptibility. These results, indicative of bystander selection, have implications for antibiotic prescribing guidelines. |
Influenza vaccine effectiveness
Ferdinands JM , Patel MM , Foppa IM , Fry AM . Clin Infect Dis 2018 69 (1) 190-191 We read with interest the article by Ray and colleagues and the accompanying editorial by Dr Lipsitch [1, 2]. Ray et al identified a 2-fold increased risk of influenza among individuals vaccinated for >5 months compared to those recently vaccinated. More than a dozen papers have reported findings of declining vaccine effectiveness (VE) with increasing time since vaccination using the test-negative design [3]. We agree with Dr Lipsitch that caution is warranted when inferring that waning immunity is the mechanistic cause of the observed decline in VE. |
Viral factors in influenza pandemic risk assessment.
Lipsitch M , Barclay W , Raman R , Russell CJ , Belser JA , Cobey S , Kasson PM , Lloyd-Smith JO , Maurer-Stroh S , Riley S , Beauchemin CA , Bedford T , Friedrich TC , Handel A , Herfst S , Murcia PR , Roche B , Wilke CO , Russell CA . Elife 2016 5 The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk. |
Temporally varying relative risks for infectious diseases: implications for infectious disease control
Goldstein E , Pitzer VE , O'Hagan JJ , Lipsitch M . Epidemiology 2016 28 (1) 136-144 Risks for disease in some population groups relative to others (relative risks) are usually considered to be consistent over time, though they are often modified by other, non-temporal factors. For infectious diseases, in which overall incidence often varies substantially over time, the patterns of temporal changes in relative risks can inform our understanding of basic epidemiologic questions. For example, recent work suggests that temporal changes in relative risks of infection over the course of an epidemic cycle can both be used to identify population groups that drive infectious disease outbreaks, and help elucidate differences in the effect of vaccination against infection (that is relevant to transmission control) compared with its effect against disease episodes (that reflects individual protection). Patterns of change in the in age groups affected over the course of seasonal outbreaks can provide clues to the types of pathogens that could be responsible for diseases for which an infectious cause is suspected. Changing apparent efficacy of vaccines during trials may provide clues to the vaccine's mode of action and/or indicate risk heterogeneity in the trial population. Declining importance of unusual behavioral risk factors may be a signal of increased local transmission of an infection. We review these developments and the related public health implications. |
Genomic epidemiology of gonococcal resistance to extended spectrum cephalosporins, macrolides, and fluoroquinolones in the US, 2000-2013.
Grad YH , Harris SR , Kirkcaldy RD , Green AG , Marks DS , Bentley SD , Trees D , Lipsitch M . J Infect Dis 2016 214 (10) 1579-1587 BACKGROUND: Treatment of Neisseria gonorrhoeae infection is empiric and based on population-wide susceptibilities. Increasing antimicrobial resistance underscores the potential importance of rapid diagnostics, including sequence-based tests, to guide therapy. However, the utility of sequence-based diagnostics depends on the prevalence and dynamics of the resistance mechanisms. METHODS: We define the prevalence and dynamics of resistance markers to extended spectrum cephalosporins (ESC), macrolides, and fluoroquinolones in 1102 resistant and susceptible clinical N. gonorrhoeae isolates collected from 2000-2013 via the CDC's Gonococcal Isolate Surveillance Project (GISP). RESULTS: Reduced ESC susceptibility (ESCRS) is predominantly clonal and associated with the mosaic penA XXXIV allele and derivatives (sensitivity 98% for cefixime, 91% for ceftriaxone), but alternative resistance mechanisms have sporadically emerged. Reduced azithromycin susceptibility (AziRS) has arisen through multiple mechanisms and shows limited clonal spread; the basis for resistance in 36% of AziRS isolates is unclear. Quinolone resistant N. gonorrhoeae (QRNG) have arisen multiple times, with extensive clonal spread. CONCLUSION: QRNG and reduced cefixime susceptibility appear amenable to development of sequence-based diagnostics, whereas the undefined mechanisms of resistance to ceftriaxone and azithromycin underscore the importance of phenotypic surveillance. The identification of multidrug-resistant isolates highlights the need for additional measures to respond to the threat of untreatable gonorrhea. |
Enhancing disease surveillance with novel data streams: challenges and opportunities
Althouse BM , Scarpino SV , Meyers LA , Ayers JW , Bargsten M , Baumbach J , Brownstein JS , Castro L , Clapham H , Cummings DAT , Del Valle S , Eubank S , Fairchild G , Finelli L , Generous N , George D , Harper DR , Hébert-Dufresne L , Johansson MA , Konty K , Lipsitch M , Milinovich G , Miller JD , Nsoesie EO , Olson DR , Paul M , Polgreen PM , Priedhorsky R , Read JM , Rodríguez-Barraquer I , Smith DJ , Stefansen C , Swerdlow DL , Thompson D , Vespignani A , Wesolowski A . EPJ Data Sci 2015 4 (1) 17 Novel data streams (NDS), such as web search data or social media updates, hold promise for enhancing the capabilities of public health surveillance. In this paper, we outline a conceptual framework for integrating NDS into current public health surveillance. Our approach focuses on two key questions: What are the opportunities for using NDS and what are the minimal tests of validity and utility that must be applied when using NDS? Identifying these opportunities will necessitate the involvement of public health authorities and an appreciation of the diversity of objectives and scales across agencies at different levels (local, state, national, international). We present the case that clearly articulating surveillance objectives and systematically evaluating NDS and comparing the performance of NDS to existing surveillance data and alternative NDS data is critical and has not sufficiently been addressed in many applications of NDS currently in the literature. |
On the relative role of different age groups in influenza epidemics
Worby CJ , Chaves SS , Wallinga J , Lipsitch M , Finelli L , Goldstein E . Epidemics 2015 13 10-16 The identification of key "driver" groups in influenza epidemics is of much interest for the implementation of effective public health response strategies, including vaccination programs. However, the relative importance of different age groups in propagating epidemics is uncertain.During a communicable disease outbreak, some groups may be disproportionately represented during the outbreak's ascent due to increased susceptibility and/or contact rates. Such groups or subpopulations can be identified by considering the proportion of cases within the subpopulation occurring before (Bp) and after the epidemic peak (Ap) to calculate the subpopulation's relative risk, RR=Bp/Ap. We estimated RR for several subpopulations (age groups) using data on laboratory-confirmed US influenza hospitalizations during epidemics between 2009 and 2014. Additionally, we simulated various influenza outbreaks in an age-stratified population, relating the RR to the impact of vaccination in each subpopulation on the epidemic's initial effective reproductive number Re(0).We found that children aged 5-17 had the highest estimates of RR during the five largest influenza A outbreaks, though the relative magnitude of RR in this age group compared to other age groups varied, being highest for the 2009 A/H1N1 pandemic. For the 2010-2011 and 2012-2013 influenza B epidemics, adults aged 18-49, and 0-4 year-olds had the highest estimates of RR, respectively.For 83% of simulated epidemics, the group with the highest RR was also the group for which initial distribution of a given quantity of vaccine would result in the largest reduction of Re(0). In the largest 40% of simulated outbreaks, the group with the highest RR and the largest vaccination impact was children 5-17. While the relative importance of different age groups in propagating influenza outbreaks varies, children aged 5-17 play the leading role during the largest influenza A epidemics. Extra vaccination efforts for this group may contribute to reducing the epidemic's impact in the whole community. |
Improving pandemic influenza risk assessment.
Russell CA , Kasson PM , Donis RO , Riley S , Dunbar J , Rambaut A , Asher J , Burke S , Davis CT , Garten RJ , Gnanakaran S , Hay SI , Herfst S , Lewis NS , Lloyd-Smith JO , Macken CA , Maurer-Stroh S , Neuhaus E , Parrish CR , Pepin KM , Shepard SS , Smith DL , Suarez DL , Trock SC , Widdowson MA , George DB , Lipsitch M , Bloom JD . Elife 2014 3 e03883 Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response. |
In vitro selection of mutants of Neisseria gonorrhoeae with elevated MIC values and increased resistance to cephalosporins
Johnson SR , Grad Y , Ganakammal SR , Burroughs M , Frace M , Lipsitch M , Weil R , Trees D . Antimicrob Agents Chemother 2014 58 (11) 6986-9 Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third generation cephalosporins. Here we report the in vitro isolation two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ. |
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