Immunity;

What’s so “special” about SARS-CoV-2 Omicron subvariants BA.4 and BA.5?

FA Manian MD, MPH, , , , , , , , , , , , , , , , Leave a comment

BA.4 and BA.5 now account for the majority of Covid cases in the U.S.1  Several concerning features of BA.4 and BA.5 when compared to earlier strains of SARS-CoV-2 include:2-6

  1. High reproductive rate or R0 ie, the average number of new infections generated by an infectious person in a totally naïve population. BA.4/5 has an estimated R0 of 18.6, according to a one report.  For comparison, the R0 for the original Wuhan variant was estimated at 3.3, for Delta  5.1, early Omicron  9.5, BA.1 13.3, mumps 12, and measles 18.  So, it’s not surprising that we are currently experiencing higher rates of SARS-CoV-2 transmission in the population than just a few weeks ago.3
  2. Suboptimal existing immunity following prior infections due to Omicron variants BA.1 and BA.2, or prior vaccinations (including 3 doses of Pfizer vaccine).2,4
  3. More efficient spread than BA.2 when studied in human lung cells invitro. 2
  4. More pathogenic than BA.2 in hamsters. 2
  5. Reduced activity of SARS-CoV-2 therapeutic monoclonal antibodies.4
  6. Antigenically distant from other SARS-CoV-2 variants, with 50 mutations, including more than 30 on the spike protein, the viral protein targeted by Covid vaccines to induce immunity.5,6

Despite these potentially ominous traits, currently there is no evidence that  BA.4 or BA.5 is inherently more likely to cause severe disease than that caused by other Omicron subvariants.   The sheer number of infected persons in the population due to high transmission rates, however, will likely translate into higher hospitalization and deaths which has already happened in many areas.

High transmission rates also mean that we should not abandon the usual public health measures (eg, social distancing, masking indoors in public spaces) and vaccination with boosters for eligible persons with the aim of reducing hospitalization and death, if not infections.  

Bonus Pearl: Did you know that BA.4 and BA.5 became dominant in South Africa in April, 2022, despite 98% of the population reportedly having some antibodies from vaccination or previous infection or both?  

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References

  1. Leatherby L. What the BA.5 subvariant could mean for the United States. NY Times, July 7, 2022. https://theconversation.com/australia-is-heading-for-its-third-omicron-wave-heres-what-to-expect-from-ba-4-and-ba-5-185598
  2. Kimura I, Ymasoba D, Tamura T, et al. Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5. bioRxiv, preprint doi: https://doi.org/10.1101/2022.05.26.493539 , posted May 26, 2022. Accessed July, 13, 2022.
  3. Esterman D. The Conversation. Australia is heading for its third Omicron wave. Here’s what to expect from BA.4 and BA.5. July 4, 2022. https://theconversation.com/australia-is-heading-for-its-third-omicron-wave-heres-what-to-expect-from-ba-4-and-ba-5-185598
  4. Tuekprakhon A, Nutalai R, Dijokaite-Guraliuc A, et al. Antibody escape of SARS-COV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.
  5. Katella K. Omicron and BA.5: A guide to what we know. YaleMedicine, July 6, 2022. https://www.yalemedicine.org/news/5-things-to-know-omicron
  6. Topol E. The BA.5 story. The takeover by this Omicron sub-variant is not pretty. Ground Truths. June 27, 2022. https://erictopol.substack.com/p/the-ba5-story

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s so “special” about SARS-CoV-2 Omicron subvariants BA.4 and BA.5?

Should patients with prior Covid receive Covid vaccine?

FA Manian MD, MPH, , , , , Leave a comment

Yes, as recommended by the CDC.  The weight of the evidence to date suggests that previously infected individuals should receive Covid vaccine to minimize their risk of acquiring Covid again for many reasons, including the following:

First, depending on the population and the variant of SARS-CoV-2 (the agent of Covid) studied, a significant proportion of infected individuals— from 5% to >35% based on some studies— fail to produce antibodies against SARS-CoV-2.1 In 1 study, lack of antibody production was associated with younger age, lower viral load and a trend toward milder symptoms.1

Second, the body of the evidence for infection-induced immunity is much more limited with less consistent findings than that for vaccine-induced immunity.2

Third, vaccination against Covid has been shown to enhance the immune response and reduce the risk of infection even in those with prior Covid.2 In fact, 1 study reported that the risk of reinfection is more than twice among those who were previously infected but not vaccinated compared to those who got vaccinated after having Covid.3  In another study, the risk of infection in adults was more than 5 times higher in unvaccinated but previously infected individuals compared to the vaccinated person who had not had an infection previously.4

Some authors5 who oppose routine vaccination of individuals previously infected with Covid have invoked a recent CDC study6 which showed that when Delta was the predominant strain, persons with prior Covid had lower rates of infection than persons who were vaccinated alone.  However, this study was performed when booster doses of Covid vaccine were not yet available to most people and before Omicron became the predominant variant. 

Bonus Pearl: Did you know that following Covid infection, neutralizing antibodies  have a biphasic decline with an initial half-life of 2-3 months followed by a slower decline thereafter?2

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References

  1. Liu W, Russell RM, Bibollet-Ruche F, et al. Predictors of nonseroconversion after SARS-CoV-2 infection. Emerg Infect Dis 2021;27:2454-58. Predictors of Nonseroconversion after SARS-CoV-2 Infection – Volume 27, Number 9—September 2021 – Emerging Infectious Diseases journal – CDC
  2. Science brief: SARS-CoV-2 infection-induced and vaccine-induced immunity. October 29, 2021. Science Brief: SARS-CoV-2 Infection-induced and Vaccine-induced Immunity | CDC
  3. Cavanaugh AM, Spicer KB, et al. Reduced risk of reinfection with SARS-CoV-2 after Covid-9 vaccination-Kentucky, may-June 2021. MMWR 2021;70:1081-83. Reduced Risk of Reinfection with SARS-CoV-2 After COVID-19 Vaccination – Kentucky, May-June 2021 – PubMed (nih.gov)
  4. Laboratory-confirmed Covid-19 among adults hospitalized with Covid-19-like illness with infection-induced or mRNA vaccine-induced SARS-CoV-2 immunity—Nine states, January-September 2021. MMWR 2021;70:1539-44. Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19–Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity — Nine States, January–September 2021 | MMWR (cdc.gov)
  5. Makary M. The high cost of disparaging natural immunity to Covid. Wall Street Journal. January 26, 2022. The High Cost of Disparaging Natural Immunity to Covid – WSJ
  6. Leon Tm, Drabawila V, Nelson L, et al. Covid-19 cases and hospitalizations by Covid-19 vaccination status and previous Covid-19 diagnosis-California and New York, May -November 2021.  MMWR 2022;71:125-31 COVID-19 Cases and Hospitalizations by COVID-19 Vaccination Status and Previous COVID-19 Diagnosis — California and New York, May–November 2021 (cdc.gov)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should patients with prior Covid receive Covid vaccine?

Are women at higher risk of Covid-19 vaccine-related adverse events?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Data to date shows a preponderance of Covid-19 vaccine-related adverse events (AEs) among women compared to men. This finding may be due to the generally more robust immunological response to infections and vaccines among women, increased reporting of AEs by women, genetic factors, microbiome differences as well as other factors.1-3

A CDC study involving mRNA vaccines (Pfizer and Moderna) during the 1st month of vaccination roll out in the US, found that nearly 80% of adverse events were reported by women.  The great majority (>90%) of these AEs were not serious and included symptoms such as headache, dizziness and fatigue.1

A JAMA study involving individuals receiving one of the mRNA vaccines found that 94% (Pfizer) and 100% (Moderna) of anaphylaxis events occurred among women. Of note, the median age was ~40 years  with the majority of anaphylaxis events were reported after the first dose. 2

Higher incidence of AEs following Covid-19 vaccination is not surprising and may be explained biologically. Women typically have a more robust immune response to infections and vaccination, both at the level of innate and adaptive immunity with higher antibody responses.  

These findings may be in part due to hormones such as estrogen which is known to enhance differentiation of dendritic cells and proinflammatory cytokine production. Other proposed mechanisms include differences in microbiome between sexes and sex-based genetic influences on humoral immune profile with the X chromosome expressing 10 times more genes than the Y chromosome, including genes that influence immunity.3

Bonus Pearl: Did you know that anaphylactic reaction to the mRNA Covid-19 vaccines is extremely rare, occurring in only 2-5 cases/ million!2

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References

  1. Gee J, Marquez P, Su J, et al. First month of Covid-19 vaccine safety monitoring—United States, December 14, 2020—January 13, 2021. MMWR 2021;70:283-88. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008e3.htm
  2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA Covid-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA 20201;325:1101-1102. https://jamanetwork.com/journals/jama/fullarticle/2776557
  3. Fischinger S, Boudreau CM, Butler AL, et al. Sex differences in vaccine-induced humoral immunity. Semin Immunopath 2019;41:239-49. https://pubmed.ncbi.nlm.nih.gov/30547182/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are women at higher risk of Covid-19 vaccine-related adverse events?

Can my patient with Covid-19 get reinfected?

FA Manian MD, MPH, , , , , , , , Leave a comment

Patients with prior history of Covid-19 have been shown to get reinfected, sometimes less severe and sometimes more severe than the first bout.1-3 What we don’t really know is how often reinfection actually occurs, either with or without symptoms.

Symptomatic reinfection with genetically distinct SARS-CoV-2 following Covid-19 has been reported from several countries, including the USA. 1  A case series of 4 patients (age range of 33-51 y) found the severity of second infection ranging from asymptomatic to more severe disease requiring hospitalization.  First infection was mild in these cases with an intervening period of 48-142 days.1  BNO News, a Dutch website, lists many more “officially confirmed cases” as well as over a thousand “suspected reinfection cases”.4

Reinfection with Covid-19 in at least some people should not be too surprising. Some may have a suboptimal immune response to the first infection (eg with mild infection) that may be short-lasting, while others may have a better response.  Even in those with adequate response, SARS-CoV-2 antibodies may drop rapidly (half-life 36 days according to one study).3 Immunity to several other seasonal respiratory coronaviruses (cousins of SARS-CoV-2) also seems short lived (as short as 6 months).5 How much other arms of the immune system besides antibodies (eg, T cell immunity) play a role in conferring longer lasting immunity remains unclear.

These findings suggest that we cannot rely on natural infection to provide us individual or herd immunity.  Immunization is likely a better answer!

Bonus Pearl: Did you know that preliminary reports suggest that antibody loss with Covid-19 is more rapid than that found for SARS-CoV-1, the agent of SARS pandemic of 2003?3

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References

  1. Iwasaki A. What reinfections mean for COVID-19. Lancet Infect Dis 2020. Published online October 12, 2020. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30783-0/fulltext
  2. Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis 2020. Published online October 12, 2020. https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30764-7.pdf
  3. Ibarrondo J, Fulcher JA, Goodman-Meza D, et al. Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19. N Engl J Med 2020; September 10. https://www.nejm.org/doi/full/10.1056/nejmc2025179
  4. Kunzman K. Contagion Live. October 12, 2020. https://www.contagionlive.com/view/us-reports-first-confirmed-covid-19-reinfection-patient. Accessed Dec 23, 2020.
  5. Edridge AWD, Kaczorowska J, Hoste ACR, et al. Seasonal coronavirus protective immunity is short-lasting. Nature Medicine 2020;26:1691-93. https://pubmed.ncbi.nlm.nih.gov/32929268/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

Can my patient with Covid-19 get reinfected?

Is my patient with Covid-19 immune to future infections due to the same virus?

FA Manian MD, MPH, , , , , , Leave a comment

Since Covid-19 is a new disease, it is unclear if our body’s immune response can protect us from future infections, and if so, for how long.

In a MedRxiv study involving 175 Covid-19 recovered patients (median age 50 y) with mild symptoms, the production of neutralizing antibodies (Nab) varied, with ~30% of patients considered to have “very low level” titers. So at least a subset of patients with mild symptoms may not produce adequate antibodies against Covid-19 despite seemingly uncomplicated recovery.  Whether these patients are at risk of re-infection with Covid-19 virus remains to be seen.1

In a study involving patients with Covid-19 (median age 62 y) of variable severity, the rate of seropositivity at 2-4 weeks was 88% or higher. However, despite development of antibodies against surface spike protein and internal nucleoproteins of SARS-CoV-2, the Covid-19 virus, viral RNA could be detected in the throat samples from a third of patients for 20 days or longer.2

In another study involving mild Covid-19 cases, despite seroconversion after 7 days in 50% of patients and after 14 days in 100% of patients, no rapid decline in pharyngeal viral load was noted. These findings raised doubts about the role of antibodies in clearing the virus.3

Somewhat more encouraging is the finding that experimentally infected monkeys rechallenged with Covid-19 virus after full recovery 28 days following initial infection seem to be protected against Covid-19.4 So there may be some protection for couple of weeks at least! 

Ultimately, whether immunity to Covid-19 will be like seasonal coronaviruses that cause common colds with unpredictable protection after 1 year, or more similar to that of SARS virus with persistence of antibodies for ~2-3 years, only time will tell. 4,5

Stay tuned!

 

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References

  1. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv preprint doi: https://doi.org/10.1101/2020.03.30.20047365
  2. To KKW, Tsang OWTY, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet 2020; March 23. https://doi.org/10.1016/S1473-3099 (20)30196-1
  3. Wolfel R, Corman VM, Gugggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature https://doi.org/10.1038/s42586-020-2196-x (2020) .
  4. Bao L, Deng W, Gao H, et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv doi: https://dli.org/10.1101/2020.03.13.990226.
  5. Callow KA, Parry HF, Sergeant M. et al. The time course of the immune response to experimental coronavirus infection of man. Epidemiol Infect 1990;105:435-46. https://www.ncbi.nlm.nih.gov/pubmed/2170159
  6. McKenna S. What immunity to COVID-19 really means? Scientific American, April 10, 2020. https://www.scientificamerican.com/article/what-immunity-to-covid-19-really-means/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is my patient with Covid-19 immune to future infections due to the same virus?

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

The weight of the evidence to date suggests that diabetes mellitus (DM) does increase the risk of pneumonia-related hospitalization.1-3

A large population-based study involving over 30,000 patients found an adjusted relative risk (RR) of hospitalization with pneumonia of 1.26 (95% C.I 1.2-1.3) among patients with DM compared to non-diabetics.  Of note, the risk of pneumonia-related hospitalization was significantly higher in type 1 as well as type 2 DM and among patients whose A1C level was ≥9.1  Another population-based study found a high prevalence of DM (25.6%) in patients hospitalized with CAP, more than double that in the population studied.2  A 2016 meta-analysis of observational studies also found increased incidence of respiratory tract infections among patients with diabetes (OR 1.35, 95% C.I. 1.3-1.4).

Not only does DM increase the risk of pneumonia-related hospitalization, but it also appears to adversely affect its outcome with increased in-hospital mortality.2 Among patients with type 2 DM,  excess mortality has also been reported at 30 days, 90 days and 1 year following hospitalization for pneumonia. 4,5 More specifically, compared to controls with CAP, 1 year mortality of patients with DM was 30% (vs 17%) in 1 study. 4

Potential reasons for the higher incidence of pneumonia among patients with DM include increased risk of aspiration (eg, in the setting of gastroparesis, decreased cough reflex), impaired immunity (eg, chemotaxis, intracellular killing), pulmonary microangiopathy and coexisting morbidity. 1,3,5,6

Bonus Pearl: Did you know that worldwide DM has reached epidemic levels, such that if DM were a nation, it would surpass the U.S. as the 3rd most populous country! 7

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References

  1. Kornum JB, Thomsen RW, RUS A, et al. Diabetes, glycemic control, and risk of hospitalization with pneumonia. A population-based case-control study. Diabetes Care 2008;31:1541-45. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  2. Martins M, Boavida JM, Raposo JF, et al. Diabetes hinders community-acquired pneumonia outcomes in hospitalized patients. BMJ Open Diabetes Research and Care 2016;4:e000181.doi:10.1136/bmjdrc-2015000181. https://drc.bmj.com/content/4/1/e000181
  3. Abu-Ahour W, Twells L, Valcour J, et al. The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies. BMJ Open Diabetes Research and Care 2017;5:e000336. https://drc.bmj.com/content/5/1/e000336. 
  4. Falcone M, Tiseo G, Russo A, et al. Hospitalization for pneumonia is associated with decreased 1-year survival in patients with type 2 diabetes. Results from a prospective cohort study. Medicine 2016;95:e2531. https://www.ncbi.nlm.nih.gov/pubmed/26844461
  5. Kornum JB, Thomsen RW, Rus A, et al. Type 2 diabetes and pneumonia outcomes. A population-based cohort study. Diabetes Care 2007;30:2251-57. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  6. Koziel H, Koziel MJ. Pulmonary complications of diabetes mellitus. Pneumonia. Infect Dis Clin North Am 1995;9:65-96. https://www.ncbi.nlm.nih.gov/pubmed/7769221
  7. Zimmet PZ. Diabetes and its drivers: the largest epidemic in human history? Clinical Diabetes and Endocrinology 2017;3:1 https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-016-0039-3  

 

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?