Missouri Department of Health & Senior Services Healt h Health Advisory April 13, 2021 Advis ory: FROM: RANDALL W. WILLIAMS, MD, FACOG DIRECTOR Updated Guidelines for the Anti-SARS-CoV-2 SUBJECT: Updated Guidelines for the Anti-SARS-CoV-2 Monoclonal Antibody Monoclonal Antibody Treatment of COVID-19 Treatment of COVID-19 SARS-CoV-2, virus causing coronavirus disease 2019 (COVID 19), has been evolving over time, resulting in genetic variation in the population of circulating April 13, 2021 viruses across the world, including the United States. Some of those variations in viral genome can cause resistance to one or more of the monoclonal antibodies This document will be updated as new (mAb) therapies authorized to treat COVID-19. The ongoing surveillance of information becomes available. The human and sewage samples by the Missouri Department of Health and Senior current version can always be viewed Services (DHSS) indicates rise in variant SARS-CoV-2 in Missouri, similar to at http://www.health.mo.gov. other states. This DHSS Health Advisory urges health care providers in Missouri The Missouri Department of Health to follow newly updated COVID-19 mAB treatment guidelines issued by the and Senior Services (DHSS) is now using four types of documents to National Institute of Health (NIH). provide important information to medical and public health According to the DHSS surveillance of variant viruses, many of the noted variants professionals, and to other interested including 159 cases of B.1.1.7 (UK origin); 4 cases of B.1.427/B.1.429 (California persons. origin) and 1 case each of B.1.351 (South African origin) and B.1.526 (New York Health Alerts convey information origin) have been identified in Missouri. During the four-week period ending of the highest level of importance which warrants immediate action or March 13, 2021, the Centers for Disease Control and Prevention (CDC) reports 7.4% of attention from Missouri health clinical specimens sequenced from Missouri for surveillance purposes were the B.1.1.7, providers, emergency responders, 6.0% were the B.1.427/B.1.429, and 0.2% were B.1.351 variants. As observed in other public health agencies, and/or the states, the number and proportion of B.1.1.7 cases in Missouri continues to increase. public. DHSS has also conducted surveillance through testing community wastewater, which is Health Advisories provide yielding informative results. Recent sewershed analysis showed that 16 of 18 locations important information for a specific incident or situation, including that with sufficient genetic material for testing have likely presence of B.1.1.7, 2 of 18 impacting neighboring states; may not having B.1.427/B.1.429, and only 2 locations having no known variant of concern require immediate action. detected. Although sequencing of SARS-CoV-2 genome from the sewage is a new Health Guidances contain science, it is showing promising results in being able to provide an early indication of comprehensive information pertaining mutations of concern. to a particular disease or condition, and include recommendations, guidelines, etc. endorsed by DHSS. Anti-SARS-CoV-2 monoclonal antibodies target SARS-CoV-2 spike protein and block virus entry into cells. Emergency Use Authorization (EUA) 90 initially authorized Health Updates provide new or emergency use of bamlanivimab (Eli Lilly) alone for the treatment of mild to moderate updated information on an incident or situation; can also provide informa- coronavirus disease 2019 (COVID19) in adults and pediatric patients (12 years of age tion to update a previously sent and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral Health Alert, Health Advisory, or testing, and who are at high risk for progressing to severe COVID-19 and/or Health Guidance; unlikely to require immediate action. hospitalization. Due to the increase in circulating viral variants in the United States, the __________________________________ FDA requested that manufacture conduct cell culture neutralization studies to assess Office of the Director the activity of bamlanivimab against these variants, and/or amino acid substitutions 912 Wildwood found in these variants. Eli Lilly provided pseudovirus data for spike protein P.O. Box 570 substitutions found in variants B.1.1.7 (UK origin), B.1.351 (South Africa origin), P.1 Jefferson City, MO 65102 (Brazil origin), B.1.427/B.1.429 (California origin), and B.1.526 (New York origin). Telephone: 800-392-0272 Obtained data indicates major reductions in susceptibility for all of the variants studied, Fax: 573-751-6041 Website: http://www.health.mo.gov except for the one originating in the UK (Table 1). 2 Table 1. Pseudovirus Neutralization Data for SARS-CoV-2 Variant Substitutions with Bamlanivimab Alone¹ Lineage with Spike Protein Key Substitutions Fold Reduction in Substitution Testeda Susceptibility B.1.1.7 (UK origin) N501Y no changeb B.1.351 (South Africa origin) E484K >2,360c P.1 (Brazil origin) E484K >2,360c B.1.427/B.1.429 (California origin) L452R >1,020c B.1.526 (New York origin)d E484K >2,360c a For variants with more than one substitution of concern, only the one with the greatest impact on activity is listed. b No change: <5-fold reduction in susceptibility. c No activity was observed at the highest concentration tested. Bamlanivimab alone is unlikely to be active against variants from this lineage. d Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021). For Eli Lilly’s combination therapy of bamlanivimab and etesevimab, the treatment fared better against all of the variants than bamlanivimab alone (Table 2). Table 2. Pseudovirus Neutralization Data for SARS-CoV-2 Variant Substitutions with Bamlanivimab and Etesevimab Together² Lineage with Spike Protein Key Substitutions Testeda Fold Reduction in Substitution Susceptibility B.1.1.7 (UK origin) N501Y no changeb B.1.351 (South Africa origin) K417N + E484K + N501Y >45c P.1 (Brazil origin) K417T + E484K + N501Y >511c B.1.427/B.1.429 (California origin) L452R 7.4 B.1.526 (New York origin)d E484K 17 a For variants with more than one substitution of concern, only the one(s) with the greatest impact on activity is(are) listed. b No change: <5-fold reduction in susceptibility. c No activity was observed at the highest concentration tested. Bamlanivimab and etesevimab together are unlikely to be active against variants from this lineage. d Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021). According to the FDA comment, given the similarities between the substitutions in B.1.351 and P.1, it is unlikely that bamlanivimab and etesevimab together will be active against these variants. Regeneron’s mAb combination of casirivimab with imdevimab showed the least reduction in susceptibility against the variants (Table 3). Table 3. Pseudovirus Neutralization Data for SARS-CoV-2 Variant Substitutions with Casirivimab and Imdevimab Together₃ Lineage with Spike Protein Key Substitutions Tested Fold Reduction in Substitution Susceptibility B.1.1.7 (UK origin) N501Ya no changec B.1.351 (South Africa origin) K417N + E484K + N501Yb no changec P.1 (Brazil origin) K417T + E484K no changec B.1.427/B.1.429 (California origin) L452R no changec B.1.526 (New York origin)d E484K no changec a Pseudovirus expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. b Pseudovirus expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V. c No change: <2-fold reduction is susceptibility. d Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021) 3 At this time, it is not known how pseudovirus data correlate with clinical outcomes. Based on findings described above and other additional information, the NIH has recently updated mAB treatment guidelines for COVID-19 (https://www.covid19treatmentguidelines.nih.gov/statement-on-anti- sars-cov-2-monoclonal-antibodies-eua/), and currently recommends:  Using one of the following combination anti-SARS-CoV-2 monoclonal antibodies to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression: o Bamlanivimab 700 mg plus etesevimab 1,400 mg; or o Casirivimab 1,200 mg plus imdevimab 1,200 mg.  There are no comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab plus etesevimab and casirivimab plus imdevimab. o There are SARS-CoV-2 variants, particularly those that contain the mutation E484K, that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known. o In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab plus etesevimab are common, some NIH Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.  Because clinical outcome data are limited and there are concerns regarding decreased susceptibility of variants, the Panel recommends against the use of bamlanivimab monotherapy. o If combination products are not available, the use of bamlanivimab monotherapy can be considered for people who meet the EUA criteria on a case-by-case basis. Missouri healthcare providers and public health practitioners: Please contact your local public health agency or the Missouri Department of Health and Senior Services’ (DHSS’) Bureau of Communicable Disease Control and Prevention at 573-751-6113 or 800-392-0272 (24/7) with questions regarding this Alert. For information on requesting SARS-CoV-2 variant testing in Missouri, please see the DHSS Health Update “Enhancing Public Health Surveillance for Variant SARSCoV-2 Viruses in Missouri” available at https://health.mo.gov/emergencies/ert/alertsadvisories/pdf/update21921.pdf. For additional information on sewershed testing, please contact the Bureau of Environmental Epidemiology at (573) 751-6102 or visit our sewershed storymap at https://storymaps.arcgis.com/stories/f7f5492486114da6b5d6fdc07f81aacf. References: 1. https://www.fda.gov/media/143603/download?utm_medium=email&utm_source=govdelivery 2. https://www.fda.gov/media/145802/download?utm_medium=email&utm_source=govdelivery 3. Fact Sheet For Health Care Providers Emergency Use Authorization (Eua) Of Regen Covtm (Casirivimab With Imdevimab) (fda.gov) Missouri Department of Health & Senior Services Healt h Health Advisory 06.23.2021 Advisory: FROM: Robert Knodell, DHSS Acting Director Emergence of Delta SUBJECT: Emergence of Delta Variant of Coronavirus Causing COVID-19 Variant of Coronavirus in USA Causing COVID-19 in USA The Missouri Department of Health and Senior Services (DHSS) is issuing this 06.23.2021 Health Advisory to provide the latest information regarding the emergence of the Delta variant. The increase in this highly transmissible variant underscores the This document will be updated as new information becomes available. The importance of continued testing for COVID-19 for patients with compatible current version can always be viewed at http://www.health.mo.gov. symptoms, as well as individuals who are not fully vaccinated and have been The Missouri Department of Health exposed to SARS-CoV-2 but may be asymptomatic. Social distancing and and Senior Services (DHSS) is now using four types of documents to appropriate masking remain very important countermeasures. Vaccination is the provide important information to medical and public health most effective and long-lasting tool for protection from this infection. The DHSS professionals, and to other interested persons. continues to encourage all eligible persons to get vaccinated against COVID-19. Health Alerts convey information of the highest level of importance which warrants immediate action or The Delta variant (B.1.617.2, formerly India variant) of COVID-19 causing attention from Missouri health providers, emergency responders, coronavirus originated and rapidly spread in India, and is emerging in the United public health agencies, and/or the public. States, as well as in many other countries. On June 15, 2021, the CDC named Delta Health Advisories provide important information for a specific variant a variant of concern (VOC) in the United States. As of mid-June 2021, the incident or situation, including that impacting neighboring states; may not CDC estimates the Delta variant is accounting for 20% of new cases in the United require immediate action. States. The variant virus proportions estimate based on the CDC sequence data of Health Guidances contain comprehensive information pertaining human samples shows the highest proportion of cases is in HHS Region 7 to a particular disease or condition, and include recommendations, (Missouri, Kansas, Iowa, and Nebraska), comprising 34.8% of all variant viruses guidelines, etc. endorsed by DHSS. detected. This is an increase from 1.6% just one month ago. Genetic surveillance of Health Updates provide new or updated information on an incident or COVID-19 cases by the Missouri DHSS in collaboration with the University of situation; can also provide informa- tion to update a previously sent Missouri detected at least one case of Delta virus in 35 counties across all regions Health Alert, Health Advisory, or Health Guidance; unlikely to require of the State. The highest proportion of Delta virus is detected in the Southwest immediate action. __________________________________ region of the State, which accounts for just over 67% of all Delta variants Office of the Director 912 Wildwood identified. The ongoing DHSS surveillance of sewage samples, most recently P.O. Box 570 Jefferson City, MO 65102 available from 23 wastewater treatment facilities across the state, reveals presence Telephone: 800-392-0272 Fax: 573-751-6041 of Delta virus at 16 locations. Website: http://www.health.mo.gov 2 Viral mutations naturally occur in the genome of many viruses, including SARS-CoV-2 which causes COVID-19. Unlike the human genome which is slow to mutate, RNA viruses, such as SARS-CoV-2, are able to quickly mutate. Once the mutation occurs, it may alter the viral function (for example, enhance receptor binding), or may have no effect on how virus functions. A new virus variant emerges when the virus develops one or more mutations that differentiate it from the predominant virus variants circulating in a population. Accumulating data shows that Delta virus may have increased binding with human ACE receptors and increased transmissibility when compared to previously emerged variant viruses. New Public Health England (PHE) research suggests the Delta variant is associated with a 64% increased risk of household transmission compared with the Alpha variant (B.1.1.7, formerly UK variant), and is 40% more transmissible outdoors. Analysis of data from Scotland just published in The Lancet indicated that Delta variant approximately doubles the risk of hospitalization compared with the Alpha variant. Variants of concern, such as Delta virus, may also reduce vaccine effectiveness, which may be evident by a high number of vaccine breakthrough cases or a very low vaccine-induced protection against severe disease. One recent study revealed that Delta variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals. A pre-print study released by PHE on May 22, 2021 found that two doses of the Pfizer-BioNTech vaccine were 88% effective against symptomatic infection with the Delta variant versus 93.4% for the Alpha variant. However, one dose was only 33% effective against symptomatic infection with the Delta variant versus 50% for the Alpha variant. The PHE data also shows the Pfizer/BioNTech vaccine is 96% effective against hospitalization, after two doses, in those who experience Delta virus infection. These new findings underscore importance of receiving two doses of COVID-19 vaccination and adhering to the typical regimen of injections. Clinical knowledge regarding differences in symptoms caused by the Delta virus infection is currently limited. According to the patient data from the UK where the Delta variant now accounts for 91% of the Covid-19 cases, disease caused by this variant may not present in typical fashion with cough and fever. An ongoing U.K.-based study (Zoe Covid Symptom Study) enables public to enter their COVID symptoms on a smartphone application for the scientists to then analyze the data. 3 Analysis of such data shows that top symptoms of Delta variant infection are headache, followed by runny nose and sore throat, while fever and cough were less common; loss of smell was not in the top ten. Most cases were in young people who had not yet been vaccinated, and that the variant appeared to be far more transmissible with every person infecting several others. Implication of such findings is that infected persons may not perceive themselves as having COVID-19 symptoms and not seek health care accordingly, and health providers may not pursue an appropriate testing. The Missouri DHSS urges health care providers and the public to be vigilant for the possibility of Delta virus infection. Social distancing and appropriate masking remain very important countermeasures. Vaccination is the most effective and long-lasting tool for protection from this infection. The DHSS continues to encourage all eligible persons to get vaccinated against COVID-19. Missouri healthcare providers and public health practitioners: Please contact your local public health agency or the Missouri Department of Health and Senior Services’ (DHSS’) Bureau of Communicable Disease Control and Prevention at 573-751-6113 or 800-392-0272 (24/7) with questions regarding this health advisory. Missouri Department of Health & Senior Services Health Health Advisory Advisory: 06.30.2021 FROM: Robert Knodell, DHSS Acting Director National Pause for the Distribution and SUBJECT: National Pause for the Distribution and Utilization of Utilization of Bamlanivimab and Etesevimab for the Treatment of Mild Bamlanivimab and to Moderate COVID-19 Etesevimab for the Treatment of Mild to Moderate COVID-19 The Missouri Department of Health and Senior Services (DHSS) received 06.30.2021 important prescribing information from Eli Lilly, manufacturer of bamlanivimab This document will be updated as and etesevimab. Content of Lilly’s notification is repeated below and can also be new information becomes available. The current version can always be found at https://www.covid19.lilly.com/assets/pdf/bam-ete/bam-ete-pause.pdf viewed at http://www.health.mo.gov. The Missouri Department of Health and Senior Services (DHSS) is now The Assistant Secretary for Preparedness and Response and the Food and Drug using four types of documents to provide important information to Administration (FDA) have paused the distribution of bamlanivimab and medical and public health professionals, and to other interested etesevimab across all 50 states within the United States effective 25 June 2021 due persons. Health Alerts convey information to reduced effectiveness against certain specific viral variants. As a result, do not of the highest level of importance which warrants immediate action or use bamlanivimab and etesevimab administered together at this time. Use other attention from Missouri health providers, emergency responders, authorized monoclonal antibodies to treat patients with mild to moderate COVID- public health agencies, and/or the public. 19. Importantly, the pause of bamlanivimab and etesevimab distribution and use is Health Advisories provide not due to any new safety concerns. important information for a specific incident or situation, including that impacting neighboring states; may not require immediate action. The Centers for Disease Control and Prevention has identified that the combined Health Guidances contain frequencies of the P.1 (Gamma) variant (first identified in Brazil) and the B.1.351 comprehensive information pertaining to a particular disease or (Beta) variant (first identified in South Africa) throughout the United States now condition, and include recommendations, guidelines, etc. exceeds 11% and is trending upward (https://www.cdc.gov/coronavirus/2019- endorsed by DHSS. Health Updates provide new or ncov/cases-updates/variant-proportions.html). Results from in vitro assays that are updated information on an incident or situation; can also provide informa- used to assess the susceptibility of viral variants to particular monoclonal antibodies tion to update a previously sent Health Alert, Health Advisory, or suggest that bamlanivimab and etesevimab administered together are not active Health Guidance; unlikely to require immediate action. against either the P.1 (Gamma) or B.1.351 (Beta) variants. These assays use Office of the Director “pseudotyped-virus-like particles” that help determine likely susceptibility of the 912 Wildwood live SARS-CoV-2 variant viruses. P.O. Box 570 Jefferson City, MO 65102 Telephone: 800-392-0272 Fax: 573-751-6041 Website: http://www.health.mo.gov 2 The duration of this pause will be determined in close coordination with the FDA and US government. If you have bamlanivimab and etesevimab at your facility, you do not need to dispose of these drugs at this time. Healthcare providers should direct questions about bamlanivimab and etesevimab to Eli Lilly and Company at 1-855-LillyC19 (1-855-545-5921). Additional information on the use of bamlanivimab and etesevimab together, including the authorized Bamlanivimab and Etesevimab Fact Sheet for Healthcare Providers, can be found at www.BAMandETE.com. Reporting Adverse Events: Per the requirements for bamlanivimab and etesevimab administration under the Emergency Use Authorization (EUA), healthcare providers are responsible for mandatory reporting of all medication errors and serious adverse events potentially related to bamlanivimab and etesevimab treatment. Refer to the Fact Sheet and www.BAMandETE.com for detailed instructions. Missouri healthcare providers and public health practitioners: Please contact your local public health agency or the Missouri Department of Health and Senior Services’ (DHSS’) Bureau of Communicable Disease Control and Prevention at 573-751-6113 or 800-392-0272 (24/7) with questions regarding this health advisory. Missouri Department of Health & Senior Services Healt h Health Advisory 07/06/2021 Advis ory: FROM: Robert Knodell, DHSS Acting Director Observed Interseasonal SUBJECT: Observed Interseasonal Respiratory Syncytial Virus Surge in Respiratory Syncytial Missouri Virus Surge in Missouri On June 10th CDC issued a health advisory to notify clinicians and caregivers about increased interseasonal respiratory syncytial virus (RSV) activity across parts of the 07/06/2021 Southern United States. This document will be updated as new information becomes available. The Each year in the United States RSV leads, on average to approximately 2.1 million current version can always be viewed at http://www.health.mo.gov. outpatient visits and 58,000 hospitalizations with 100-500 deaths among children The Missouri Department of Health younger than 5 years old, and 177,000 hospitalizations and 14,000 deaths among and Senior Services (DHSS) is now adults 65 years and older. using four types of documents to provide important information to Missouri is experiencing a similar, unexpected off-season surge in RSV cases. medical and public health professionals, and to other interested According to national RSV surveillance data, as well as data from Missouri’s persons. children’s hospitals across the state, the increase in RSV cases continues statewide. Health Alerts convey information Infection rates are currently comparable to the regular RSV season levels seen in of the highest level of importance previous years. Typically, the RSV season onset ranges from mid-September to which warrants immediate action or mid-November; peak season ranges from late-December to mid-February, and attention from Missouri health providers, emergency responders, season offset ranges from mid-April to mid-May in most of the country. public health agencies, and/or the public. Missouri DHSS recommends extending monthly preventive palivizumab for infants Health Advisories provide at risk for severe RSV disease in order to ensure continued protection during this important information for a specific unexpected surge. Since the duration of this surge cannot be predicted, extension of incident or situation, including that impacting neighboring states; may not the palivizumab preventive treatment coverage for the period of July-August, 2021 require immediate action. is indicated. Health Guidances contain comprehensive information pertaining CDC encourages broader testing for RSV among patients presenting with acute to a particular disease or condition, respiratory illness who test negative for SARS-CoV-2, the virus that causes and include recommendations, guidelines, etc. endorsed by DHSS. COVID-19. RSV can be associated with severe disease in young children and older Health Updates provide new or adults. This health advisory also serves as a reminder to healthcare personnel, updated information on an incident or childcare providers, and staff of long-term care facilities to avoid reporting to work situation; can also provide informa- while acutely ill – even if they test negative for SARS-CoV-2. tion to update a previously sent Health Alert, Health Advisory, or Health Guidance; unlikely to require immediate action. __________________________________ Office of the Director 912 Wildwood P.O. Box 570 Jefferson City, MO 65102 Telephone: 800-392-0272 Fax: 573-751-6041 Website: http://www.health.mo.gov 2 Additional recommendations include: 1. Clinicians and caregivers should be aware of the typical clinical presentation of RSV for different age groups. 2. Clinicians should consider testing patients with a negative SARS-CoV-2 test and acute respiratory illness or the age-specific symptoms presented above for non-SARS-CoV-2 respiratory pathogens, such as RSV. Real-time reverse transcription-polymerase chain reaction (rRT-PCR) is the preferred method for testing for respiratory viruses. 3. Clinicians should report laboratory-confirmed RSV cases and suspected clusters of severe respiratory illness to local and state health departments according to their routine reporting requirements. ONLY outbreaks are reportable in Missouri. 4. Healthcare personnel, childcare providers, and staff of long-term care facilities should avoid reporting to work while acutely ill – even if they test negative for SARS-CoV-2. 5. Clinicians can review weekly updates to the NREVSS website and refer to surveillance data collected by local hospitals and health departments for information on RSV circulation trends in their area. ***Missouri healthcare providers and public health practitioners: Please contact your local public health agency or the Missouri Department of Health and Senior Services’ (DHSS’) Bureau of Communicable Disease Control and Prevention at 573-751-6113 or 800-392-0272 (24/7) with questions regarding this Advisory.***