Breakthrough infection

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]

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]

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]

In April 2021, scientists reported that in a cohort of 417 vaccinated persons, two women had breakthrough infections as of publication and identified 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]

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]

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]

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]

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]

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]