Breakthrough infection

A breakthrough infection is a case of illness in which a vaccinated individual becomes infected with the illness, because the vaccine has failed to provide complete immunity against the pathogen.[1] Breakthrough infections have been identified in individuals immunized against a variety of diseases including mumps, varicella (Chicken Pox), influenza, and COVID-19.[2][3][4] The characteristics of the breakthrough infection are dependent on the virus itself. Often, infection of the vaccinated individual results in milder symptoms and shorter duration than if the infection were contracted naturally.[5]

Causes of breakthrough infections include biological factors in the recipient, improper administration or storage of vaccines, mutations in viruses and blocking antibodies, and other factors. For these reasons, vaccines are rarely 100% effective. A 2021 study found the common flu vaccine provided immunity to the flu in 58% of recipients.[6] The measles vaccine fails to provide immunity to 2% of children that receive the vaccine. However, if herd immunity exists, it typically prevents individuals who are ineffectively vaccinated from contracting the disease.[7] Accordingly, herd immunity reduces the number of breakthrough infections in a population.[8]

By disease

Varicella

The varicella vaccine is 85% effective at preventing varicella (chickenpox) infection.[9] However, 75% of individuals that are diagnosed with breakthrough varicella exhibit milder symptoms than individuals that are not vaccinated.[5] These individuals with mild varicella have low fevers, fewer than 50 lesions on their skin and a maculopapular rashes. In contrast, unvaccinated individuals typically have a fever of 102, 200-500 skin lesions and macules (lesions that are not elevated) evolve to papules and vesicular lesions.[5][10] Additionally, infection in unvaccinated individuals tends to last for a longer period of time than in individuals who have been infected.[5]

The majority of cases of breakthrough varicella are attributed to the failure of an individual to uptake the varicella vaccine.[9] Therefore, to prevent breakthrough infections, it is proposed that children receive a second dose of varicella vaccine less than a year after getting their first dose.[9]

Mumps

The mumps vaccine is a component of the Measles, Mumps and Rubella vaccine (MMR).[11] The mumps vaccine, specifically, is 88% effective at preventing mumps.[12] Individuals with breakthrough cases of mumps have fewer serious complications from the infections as compared to individuals unvaccinated for mumps.[13] These complications include the development of aseptic meningitis and encephalitis.[13]

The cause of breakthrough mumps is not currently completely understood. Evolution of the virus (antigenic drift) is thought to explain the majority of breakthrough cases.[13] Other theories suggest that memory T lymphocytes play a role in the development of breakthrough infections.[13]

Hepatitis B

Breakthrough cases of Hepatitis B are primarily attributed to mutations in the Hepatitis B virus (HBV) that make HBV surface proteins unrecognizable to antibodies produced from the HBV vaccine.[14][15][16] Viruses with such mutations are called “vaccine escape mutants”. Breakthrough infections may also be caused by delayed vaccination, immunosuppression, and maternal viral load.[15] It is possible for an individual to have breakthrough infection of HBV but be asymptomatic.[14]

COVID-19

In April 2021, scientists reported that in a cohort of 417 vaccinated persons two women had vaccine breakthrough infections as of publication and identify their variants' viral mutations.[17][18] In the same month, the CDC reported that in the United States there were 5,814 COVID-19 breakthrough infections, and 74 deaths among the more than 75 million people fully vaccinated for the COVID-19 virus.[19][20][21][22][23][24] In July 2021, scientists reported that in an outbreak of the SARS-CoV-2 Delta variant, associated with large public gatherings, 74% of infections occurred in fully vaccinated people.[25][26]

Characteristics

Age

As a person ages, their immune system undergoes a series of changes, in a process referred to as immunosenescence.[27] Notable among these changes is a decreased production of naive T cells and naive B cells.[28] The reduced number of naive lymphocytes (T and B cells) is attributed to the fact that the telomeres in hematopoietic stem cells (HSCs), degenerate over time and, consequently, limit the proliferation of HSCs and production of lymphoid progenitor cells.[27][28] This is compounded by the fact that, with time, HSCs tend to favor the production of myeloid progenitor cells over lymphoid progenitor cells.[28] Mature lymphocytes are also unable to proliferate indefinitely.[27] Compounded, the reduction in number of naive lymphocytes and limitations of the proliferative abilities of mature lymphocytes contribute to a limited number and variety of lymphocytes to respond to pathogens presented in a vaccine.[28]

Indeed, vaccines, including the influenza vaccine, Tdap, and pneumococcal vaccines, are less effective in adults over the age of 65.[28][29] Nevertheless, the CDC recommends that elderly adults get the flu vaccine because influenza infection is particularly dangerous in this population and vaccine provides at least a moderate level of immunity to the flu virus.[29]

Antibody interference

The presence of maternal antibodies in infants limits the efficacy of inactivated, attenuated and subunit vaccines.[30] Maternal antibodies can bind to epitopes on the proteins produced by the virus in the vaccination. The recognition of viral proteins by maternal antibodies neutralizes the virus.[31] Further, the maternal antibodies outcompete B cell receptors on the infant's B cells for binding to the antigen. Thus, an infant's immune system is not highly activated and the infant produces fewer antibodies.[8][30] Even when B cells do bind to the pathogen, immune response is still frequently repressed. If B cell receptors bind to the antigen and Fc receptor simultaneously bind to the maternal antibody, the Fc receptors send a signal to B cell receptors that inhibits cell division.[31] Because the infant's immune system is not stimulated and B cell division is inhibited, few memory B cells are produced. The level of memory B-cells is not adequate to ensure an infant's lifelong resistance to the pathogen.[30][31]

In most infants, maternal antibodies disappear 12–15 months after birth, so vaccines administered outside this window are not compromised by maternal antibody interference.[8]

Longevity of memory B cells

When an individual is vaccinated against a disease, the individual's immune system is triggered and memory B cells store the specific antibody response.[8] These cells remain in circulation until the pathogen infection is cleared. Because the telomeres in genes degenerate after each successive cell division, lymphocytes, including memory B cells are not capable of proliferating indefinitely.[27] Typically, the cells live for multiple decades, but there is variation in the longevity of these cells depending on the type of vaccine they were stimulated with and the vaccine dosage.[31] The reason for the differences in the longevity of memory B cells is currently unknown. However, it has been proposed that the differences in memory B cell longevity are due to the speed at which a pathogen infects the body and, accordingly, the number and type of cells involved in the immune response to the pathogen in the vaccine.[32]

Virus evolution

When a person is vaccinated, their immune system develops antibodies that recognize specific segments (epitopes) viruses or viral-induced proteins. Over time, however, viruses accumulate genetic mutations which can impact the 3D structure of viral proteins.[33] If these mutations occur in sites that are recognized by antibodies, the mutations block antibody binding which inhibits the immune response.[34] This phenomenon is called antigenic drift. Breakthrough infections of Hepatitis B and mumps are partially attributed to antigenic drift.[13][15]

Vaccine quality and administration

Vaccines may fail to provide immunity if the vaccine is of poor quality when administered. A vaccine loses potency if it is stored at the incorrect temperature or if it is kept after the expiration date.[35] Similarly, appropriate vaccine dosage is essential to ensuring immunity. Vaccine dosage is dependent on factors including a patient's age and weight.[35] Failure to account for these factors can lead to patients receiving an incorrect amount of vaccination. Patients that receive a lower dose than recommended of a vaccine do not have an adequate immune response to the vaccine to ensure immunity.[31]

In order for a vaccine to be effective, an individual must respond to the pathogens in a vaccine through the adaptive branch of the immune system and that response must be stored in an individual's immunological memory.[8] It is possible for an individual to neutralize and clear a pathogen through the humoral response without activating the adaptive immune response.[8] Vaccines with weaker or fewer strains of a pathogen, as is the case when a vaccine is of poor quality when administered, may primarily elicit the humoral response, and, thus, fail to ensure future immunity.[8]

References

  1. ↑ CDC (2020-02-11). "COVID-19 Vaccination". Centers for Disease Control and Prevention. Retrieved 2022-01-06.
  2. ↑ "Factsheet for health professionals". ecdc.europa.eu. Archived from the original on 2017-02-24. Retrieved 2017-02-24.
  3. ↑ "Chickenpox | Clinical Overview | Varicella | CDC". www.cdc.gov. Retrieved 2017-02-24.
  4. ↑ "Use of Antivirals | Health Professionals | Seasonal Influenza (Flu)". www.cdc.gov. Retrieved 2017-02-24.
  5. 1 2 3 4 "Chickenpox (Varicella)". Center for Disease Control and Prevention. 1 July 2016.
  6. ↑ Osterholm, Michael T; Kelley, Nicholas S; Sommer, Alfred; Belongia, Edward A (2012). "Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis". The Lancet Infectious Diseases. 12 (1): 36–44. doi:10.1016/s1473-3099(11)70295-x. PMID 22032844.
  7. ↑ Fine, P.; Eames, K.; Heymann, D. L. (2011-04-01). ""Herd Immunity": A Rough Guide". Clinical Infectious Diseases. 52 (7): 911–916. doi:10.1093/cid/cir007. ISSN 1058-4838. PMID 21427399.
  8. 1 2 3 4 5 6 7 Owen, Judith; Punt, Jenni; Stranford, Sharon (2013). Kuby Immunology (7th ed.). New York City, New York: W.H. Freeman and Company. pp. 576–578. ISBN 978-14292-1919-8.
  9. 1 2 3 Papaloukas, Orestis; Giannouli, Georgia; Papaevangelou, Vassiliki (2014-03-01). "Successes and challenges in varicella vaccine". Therapeutic Advances in Vaccines. 2 (2): 39–55. doi:10.1177/2051013613515621. ISSN 2051-0136. PMC 3991154. PMID 24757524.
  10. ↑ "Pinkbook | Varicella | Epidemiology of Vaccine Preventable Diseases | CDC". www.cdc.gov. Retrieved 2017-02-17.
  11. ↑ "Factsheet for health professionals". ecdc.europa.eu. Archived from the original on 2017-02-24. Retrieved 2017-02-17.
  12. ↑ "Mumps | Cases and Outbreaks | CDC". www.cdc.gov. Retrieved 2017-02-17.
  13. 1 2 3 4 5 Latner, Donald R.; Hickman, Carole J. (2015-05-07). "Remembering Mumps". PLOS Pathogens. 11 (5): e1004791. doi:10.1371/journal.ppat.1004791. ISSN 1553-7374. PMC 4423963. PMID 25951183.
  14. 1 2 Seed, Clive R.; Jones, Ngaire T.; Pickworth, Anne M.; Graham, Wendy R. (2012-01-01). "Two cases of asymptomatic HBV "vaccine breakthrough" infection detected in blood donors screened for HBV DNA". Medical Journal of Australia. 196 (10): 651–652. doi:10.5694/mja11.11589. ISSN 0025-729X. PMID 22676882. S2CID 23463146.
  15. 1 2 3 Chang, Mei-Hwei (2010). "Breakthrough HBV infection in vaccinated children in Taiwan: surveillance for HBV mutants". Antiviral Therapy. 15 (3 Part B): 463–469. doi:10.3851/imp1555. PMID 20516566.
  16. ↑ Coleman, Paul F. (2017-02-17). "Detecting Hepatitis B Surface Antigen Mutants". Emerging Infectious Diseases. 12 (2): 198–203. doi:10.3201/eid1203.050038. ISSN 1080-6040. PMC 3293431. PMID 16494742.
  17. ↑ Howard, Jacqueline. "Only 2 'breakthrough' infections among hundreds of fully vaccinated people, new study finds". CNN. Retrieved 11 May 2021.
  18. ↑ Hacisuleyman, Ezgi; Hale, Caryn; Saito, Yuhki; Blachere, Nathalie E.; Bergh, Marissa; Conlon, Erin G.; Schaefer-Babajew, Dennis J.; DaSilva, Justin; Muecksch, Frauke; Gaebler, Christian; Lifton, Richard; Nussenzweig, Michel C.; Hatziioannou, Theodora; Bieniasz, Paul D.; Darnell, Robert B. (21 April 2021). "Vaccine Breakthrough Infections with SARS-CoV-2 Variants". New England Journal of Medicine. 384 (23): 2212–2218. doi:10.1056/NEJMoa2105000. PMC 8117968. PMID 33882219.
  19. ↑ Gilbert, Ben; Brubeck, Hilary (15 April 2021). "CDC: 5,800 COVID-19 infections, 74 deaths in the more than 75 million fully vaccinated people". Business Insider. Retrieved 18 April 2021.
  20. ↑ Krieger, Lisa M. (15 April 2021). "COVID vaccines: The mystery of "breakthrough" infections after shots - CDC reports 5,800 COVID-19 infections, 74 deaths in fully vaccinated people". The Mercury News. Retrieved 18 April 2021.
  21. ↑ Tinker, Ben; Fox, Maggie (15 April 2021). "CDC reports 5,800 COVID-19 infections, 74 deaths in fully vaccinated people". Orange County Register. Retrieved 18 April 2021.
  22. ↑ Masson, Gabrielle (15 April 2021). "5,800 COVID-19 infections detected among 77 million fully vaccinated people: CDC". Beckers Hospital Review. Retrieved 18 April 2021.
  23. ↑ May, Brandon (15 April 2021). "COVID-19 Infection After Vaccine is Rare But Possible, CDC Says". BioSpace. Retrieved 18 April 2021.
  24. ↑ Whelan, Robbie (15 April 2021). "CDC Identifies Small Group of Covid-19 Infections Among Fully Vaccinated Patients - Incidence is rare, occurring in only 0.008% of cases and in line with expectations". The Wall Street Journal. Retrieved 18 April 2021.
  25. ↑ Wadman, Meredith (4 August 2021). "What does the Delta variant have in store for the United States? We asked coronavirus experts". Science News. Retrieved 2021-08-23. In the Massachusetts outbreak, fully vaccinated people accounted for 74% of nearly 469 COVID-19 cases.
  26. ↑ Brown, Catherine M. (2021). "Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings — Barnstable County, Massachusetts, July 2021". MMWR. Morbidity and Mortality Weekly Report. 70 (31): 1059–1062. doi:10.15585/mmwr.mm7031e2. ISSN 0149-2195. PMC 8367314. PMID 34351882. S2CID 236935466.
  27. 1 2 3 4 Lord, Janet M. (2013-06-12). "The effect of aging of the immune system on vaccination responses". Human Vaccines & Immunotherapeutics. 9 (6): 1364–1367. doi:10.4161/hv.24696. ISSN 2164-5515. PMC 3901832. PMID 23584248.
  28. 1 2 3 4 5 Goronzy, Jörg J; Weyand, Cornelia M (2013). "Understanding immunosenescence to improve responses to vaccines". Nature Immunology. 14 (5): 428–436. doi:10.1038/ni.2588. PMC 4183346. PMID 23598398.
  29. 1 2 "Vaccine Effectiveness - How Well Does the Flu Vaccine Work? | Seasonal Influenza (Flu) | CDC". www.cdc.gov. Retrieved 2017-02-23.
  30. 1 2 3 Edwards, Kathryn M. (2015-11-25). "Maternal antibodies and infant immune responses to vaccines". Vaccine. Advancing Maternal Immunization Programs through Research in Low and Medium Income Countries. 33 (47): 6469–6472. doi:10.1016/j.vaccine.2015.07.085. PMID 26256526.
  31. 1 2 3 4 5 Siegrist, Claire-Anne (2013). "Vaccine Immunology". Vaccines. Elsevier. ISBN 9781455700905.
  32. ↑ "Top 20 Questions about Vaccination | History of Vaccines". www.historyofvaccines.org. Retrieved 2017-02-15.
  33. ↑ Fleischmann, W. Robert (1996-01-01). Baron, Samuel (ed.). Medical Microbiology (4th ed.). Galveston (TX): University of Texas Medical Branch at Galveston. ISBN 978-0963117212. PMID 21413337.
  34. ↑ "Viruses and Evolution | History of Vaccines". www.historyofvaccines.org. Retrieved 2017-02-11.
  35. 1 2 Hamborsky, Jennifer; Kroger, Andrew; Wolfe, Charles (2013). Epidemiology and Prevention of Vaccine Preventable Diseases. Washington D.C.: Center for Disease Control and Prevention.
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