News & Views: Nirsevimab Means Brushing Up on Passive Immunity Talking Points

With the availability of nirsevimab (Beyfortus™) to protect babies from respiratory syncytial virus (RSV), we are likely to find ourselves in conversations about the difference between this monoclonal-antibody-based product and vaccines. Said another way, we will be doing some talking about passive immunity. So, we thought this would be a good time to brush up on some immunology and gather resources to help!

Is nirsevimab a vaccine?

No. Vaccines present a weakened or inactivated form of a pathogen to cause the recipient to generate their own immune response against it. This is called active immunity. Nirsevimab, on the other hand, delivers antibodies that can bind to RSV and prevent an infection. This is passive immunity because the “immunologic agent” (i.e., the antibodies) was not produced by the person being protected.

Active versus passive immunity

While both active and passive immunity offer protection in the form of prevention, they differ in a few significant ways. First, as described above, the source of immunity differs. Second, and related, this means the composition of immunity differs. When someone makes an immune response on their own, that response is characterized by more than antibodies. They are also armed with memory B and T cells that are specific for the pathogen. So, if they are exposed in the future, their immune system will more quickly respond and stop the infection. In contrast, passive immunity is the delivery of antibodies generated by someone else, so no memory immunity exists. And this point informs the third difference between active and passive immunity — length of protection. In both cases, antibodies are short-lived (weeks to months), so over time, they will diminish to a point of not being protective. For people protected by passive immunity, this means their immune system will again be naïve to the pathogen; however, for those protected by active immunity, immunologic memory offers long-term protection.

So what is the benefit of passive immunity?

Simply put, speed. Active immunity takes time to develop, whereas passive immunity takes advantage of the immunologic work having been completed by someone else’s immune system (or prior production in a lab). During an active immune response, it takes several days to a week for early antibodies to appear, and the first antibodies generated are not the “best” antibodies. What does that mean exactly? Well, as our immune system fights an infection, the antibodies that are generated become more specific for the pathogen over time. This is called affinity maturation. Think of it like sculpting stone or carving wood — the first several passes are working toward a general shape and size, but with each pass, the work gets more detailed. Antibodies generated by our immune system are the same. Indeed, this is why some vaccines are given as multiple doses spaced over longer periods of time. For example, by giving the second dose of HPV vaccine six to 12 months after the first, the immune response to the second dose will be generated by memory cells that are more specific and will, therefore, produce higher quality antibodies. Likewise, the memory cells that remain after the second exposure will be more specific, so when the individual is exposed naturally, the immune response will be more effective in responding to the infection.

Sometimes, however, people don’t have the luxury of waiting for their immune system to respond. They may be too ill, or they may be at risk of becoming severely ill if they wait. An example of the former was the use of serum antibody treatments for the sickest patients early during the COVID-19 pandemic. An example of the latter is nirsevimab because young babies are at greater risk of experiencing severe disease when infected with RSV.

The role for passive immunity

Despite its limitations, passive immunity is important in specific circumstances. In the case of COVID-19 serum antibody preparations, we were still learning what treatments worked, and we didn’t have a vaccine. In the case of nirsevimab, we have yet to successfully create an effective RSV vaccine for babies. But, these are not the only situations during which we benefit from passive immunity:

• Maternal antibodies – Every baby benefits from antibodies generated by their mother’s immune system. These antibodies cross the placenta and are delivered in breast milk, and they protect the baby in the first months after birth when they are exposed to a steady onslaught of potential pathogens. Indeed, the early immunization schedule (think 2 mo., 4mo., and 6 mo. vaccines) is designed to generate active immunity during the period when a baby enjoys passive immunity from maternal antibodies, so that by the time passive immunity wanes, the baby’s immune system is ready to stave off the most dangerous diseases. In contrast, live, weakened viral vaccines, like MMR and varicella (chickenpox), are delayed until about 1 year of age, so that maternal antibodies do not interfere with the generation of immunity as the vaccine virus reproduces.
• Situations not conducive to vaccination – In some instances, vaccination doesn’t make sense because the likelihood for exposure is so low. For example, antivenin treatments are appropriate to treat people after a poisonous snake bite because the antibodies can prevent the poisons from causing harm, but so few people are bitten that it would not make sense to develop a vaccine to protect large portions of the population.
  
  Another, and more widespread, use of antibody treatments is biologics. Biologics are treatments that target specific parts of the immune system, often overactive parts. Many, but not all, biologics are monoclonal antibody treatments. In these situations, the antibodies can help control an immune response against one’s own body (autoimmune conditions) or a transplanted organ. Maybe someday, new technologies will address these situations in a more permanent way, but for now, biologics offer an opportunity to make antibodies work for affected individuals. It is worth noting, however, that in the case of biologics, these treatments often hinder the immune response to pathogens, leaving these individuals susceptible to different concerns.
• No vaccine – We collectively experienced COVID-19, a situation in which we were learning about a new pathogen and how to treat and prevent it in real time. It was a novel, “close-to-home” experience for many, but the use of passive immunity as a defense was not historically unique. Indeed, passive immunity was the approach used in some of the earliest attempts to protect ourselves against deadly diseases. Before Jenner’s smallpox vaccine, variolation was the common practice of taking material from the sores of someone who had a mild case of smallpox and inoculating it into a person who had not had smallpox.
  
  Likewise, in 1890, before a diphtheria vaccine was available, antitoxins (antibodies against toxins, or poisons, produced by the bacteria) were found to protect against diphtheria. The toxins produced during a diphtheria infection cause tissues in the airway to die. These dead tissues block the transfer of air, leading affected individuals to suffocate. Indeed, diphtheria was commonly referred to as “the strangling angel of children” for the manner of death it caused.
  
  In the case of diphtheria antitoxin, the antibodies were made in horses, since horses did not suffer the fate of people infected with the bacteria. The antibody-rich serum was purified from the horse blood and administered during outbreaks. The famous story of Balto and the Alaskan Iditarod is one of getting this life-saving treatment to the city of Nome, Alaska, during a diphtheria outbreak in 1925. The toxoid-based diphtheria vaccine was developed in the early 1920s and adjuvanted with aluminum in 1926. The toxoid vaccine was not widely used until the 1930s.

Today’s antibody-based treatments

Diphtheria antitoxin was produced in horses. Today’s antivenins are as well. Initial COVID-19 antibody treatments were from people who had recovered from the infection. When antibodies are produced in an individual or an animal, the quantity of antibodies contained in one dose are not all the same. They attach to different parts of the pathogen, and as described above related to affinity maturation, some antibodies are better than others. That is, they attach to the pathogen more strongly than others. The result is that some mixtures of antibodies are more effective than others, and consistent quality of production is virtually impossible.

To create antibody mixtures that are consistently effective, many of the antibody-based treatments used today are so-called monoclonal antibody preparations, meaning they are composed of only a single, effective antibody type. Monoclonal antibody products were originally made by fusing mouse spleen cells that secreted the antibody of interest with mouse myeloma cells, which allowed the combined cells, or hybridomas, to grow indefinitely in the lab. Today, several methods exist for creating human monoclonal antibody products, including recombinant DNA technology, which is how nirsevimab (Beyfortus) is made. The gene for the RSV antibody is added to Chinese hamster ovary (CHO) cells, so that as the cells reproduce, the antibody is also made. The antibodies are purified and mixed with some amino acids, sugar, and polysorbate 80 to keep the preparation stable. Water is used for injecting it.

Hopefully, now as you talk to families about the opportunity to protect their babies from RSV, you’ll be able to use some of these examples to talk about our long history of relying on passive immunity.

Additional resources

• Active and passive immunity, including information about maternal antibodies
• Vaccines and biologics: What you should know
• A race against time: How do antibodies work (Vaccine Makers Project Animation Expedition #2)
• Modern day Iditarod race commemorates the lifesaving run in 1925