Cold Agglutinin Disease and Vaccinations

Vaccination or immunization is complicated in individuals with cold agglutinin disease (CAD) and must be done with extreme caution because their immune systems are compromised. While it is important to vaccinate and prevent life-threatening infections in CAD patients, it is also critical to take care that the vaccination does not lead to complications.

How vaccines work

Vaccines contain either dead or alive-but-weakened bacteria or viruses that are generally given to children or adults who are at risk of infections. They generate an immune response, which is mild but enables the immune system to recognize and combat future infections.

Vaccines against some pathogens such as the polio virus need to be given only once in a lifetime to be protective while others, such as the flu virus, must be repeated yearly. Many vaccines need to be given twice or three times over the years as booster doses so that the immune system develops a memory response against a particular pathogen. This immune system memory would then be sufficient to protect the individual for life.

Vaccination and CAD

CAD can be a primary disease caused by an underlying B-cell lymphoproliferative disorder, or it can occur as a secondary disease as a result of bacterial or viral infections, other autoimmune disorders, or cancer. In both cases, autoantibodies called cold agglutinins are generated by immune cells called B cells and target red blood cells.

Because vaccination mimics infection, in rare cases, it can cause CAD. For example, a study published in the journal Clinical Case Reports in August 2019 reported that an adult patient developed cold agglutinin-induced hemolytic anemia because of pneumococcal vaccination. The cold agglutinins were raised against the ‘Pr’ protein, which is found on the surface of the red blood cells and is very similar to surface proteins produced by bacteria such as pneumonia-causing Pneumococcus bacteria.

In a few case studies, the diphtheria-pertussis-tetanus (DPT) vaccine has been implicated in the development of life-threatening CAD-related hemolytic anemia because of the production of an autoantibody against “Pr” protein with a high thermal amplitude of 37oC. Among the six cases that have been reported so far, two occurred after initial immunization and four were reported after booster doses (second or third immunization).

While these cases are rare, the reports suggest that people must be closely monitored for probable symptoms of CAD after vaccination and that special caution must be taken after vaccinating CAD patients. As a general rule, it is recommended that individuals with CAD not be vaccinated with live vaccines but with dead ones.

Vaccination and novel CAD therapies

Among the novel targets in CAD therapy are proteins of the complement system, which plays an important role in the destruction of red blood cells. These include treatments such as eculizumab, BIVV009, and APL-2, which inhibit C1s, C5, and C3 proteins of the complement system, respectively. However, blocking the complement system can make CAD patients vulnerable to infections, especially against certain types of bacteria, such as those causing meningitis. To overcome this problem, before starting treatment with these medications, vaccination against meningitis is mandatory to reduce the risk of infection.


Last updated: Aug. 17, 2019


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