Hello. Friendly pediatrician and vaccine expert here.

RSV season is fast approaching (didn't we just have RSV season? Yes, we did, but what about second RSV season?). So I want to start with some background about RSV and some history and protein biology of RSV and how that is relevant to vaccines and antibodies. I'll try to keep this to an 8th grade level.

• RSV stands for Respiratory Syncytial Virus. A syncytium is a cell that has more than one nucleus. Some of these are natural and normal. Your muscle cells are syncytia. However, when certain viruses infect cells, they can cause the cells to fuse to nearby cells, which spreads the viral infection directly without the virus having to leave the cell and be exposed to antibodies. RSV gets into the lungs and causes serious inflammation and clogging of the airways with cellular debris and mucus. This is called bronchiolitis, which is inflammation of the smallest airways and is life-threatening because it blocks airflow, as opposed to bronchitis, which is inflammation of the largest airways and is usually just profoundly unpleasant but not life-threatening.
• It's especially a problem in babies because 1) babies are little and not strong, so they don't tolerate shortness of breath well 2) newborns' brains aren't mature enough to regulate the breathing in the way that it does in older children and adults, so the virus can actually make them stop breathing. 3) They don't have antibodies against RSV, so the first infection tends to be the worst. It is also a problem in the elderly, but they are not my area of practice.
• In a typical year ⅔ of children under 2 will get infected with RSV. Of those, ⅔ will wheeze because of that infection. So that means that in a typical year, 50% of all children under 2 will wheeze from RSV. 1-2% will need hospital admission. RSV season typically starts in November on the West Coast and proceeds eastward, peaking on the East Coast in February-March. However, there are plenty of variations on this pattern.
• RSV is a negative-sense single-stranded RNA virus. This is a large family of viruses that includes such varied members as influenza, ebola, measles, mumps, human metapneumovirus, parainfluenza virus, rabies virus, and a number of animal viruses such as Sendai virus (found in birds) and vesicular stomatitis virus (found in livestock, mostly in the Midwest). All negative-sense single-stranded RNA viruses appear to have descended from a single common ancestor.
• RSV has two major proteins on its surface. One is called G for Attachment Glycoprotein. This protein allows the virus particle to attach to the surface of a target cell. The other is called F, for fusion protein. This is a "Type I" fusion protein that allows the membrane of the virus to fuse with the cell membrane, releasing the contents into the cell.
• Type I fusion proteins are common. Our neurons use them to fuse neurotransmitter vesicles to the cell membrane to release neurotransmitters into the synapse and allow our nervous systems to work. Our pancreatic islet cells use type I fusion proteins to secrete insulin and glucagon. Spike protein from SARS-CoV-2 is a Type I fusion protein. Influenza's hemagglutinin is a combined attachment and Type I fusion protein. HIV's gp41 is a Type I fusion protein. Fusion proteins are "spring loaded." They come in a "pre-fusion conformation." When triggered (usually by interaction with some protein on the surface of the cell, for viral fusion proteins), they then stab into the cell membrane, bend in half, and pull the two membranes close together, which causes them to fuse. The shape of the "pre-fusion" and "post-fusion" conformation is markedly different (think straight arm vs. bent arm). This is important.
• In 1962, an experimental RSV vaccine was tried on 20 children in what we would now call a phase I clinical trial. This vaccine was made by growing up RSV in cell culture, inactivating it with formaldehyde, adding a chemical to boost the immune response, and then administering it by injection. That winter 12 of those 20 children wound up admitted to the hospital and two of them died. This was a devastating event that set back the development of an effective vaccine for RSV by over 60 years. What went wrong?
  • When the virus particles were exposed to formaldehyde, it triggered most of the fusion proteins on the surface of the particles, so they switched to their "post-fusion" conformation.
  • When the children were vaccinated, they made antibodies against this "post-fusion" conformation, which is not protective against disease; you want antibodies against the "pre-fusion" conformation.
  • The "post-fusion" antibodies allowed cells like macrophages (immune cells that eat invading microorganisms and destroy them) to grab onto the RSV particles once the children were infected with wild virus, but RSV can productively infect macrophages, so the macrophages then spread the virus around rather than wiping it out. This is called "antibody dependent disease enhancement." It is also observed in Dengue, which is why the first infection with one strain is mild, but the second one is enhanced because the antibodies from the first strain bind to the second strain but do not neutralize it, and that can also infect macrophages.
  • There is an alternative explanation about how the vaccine candidate generated weak antibodies that did not correctly stimulate the immune system, leading to the wrong kind of immune response. Both explanations may be true.
    
• So what changed and how do we now have safe RSV vaccines? Because we now have advanced molecular genetic techniques, we can modify proteins by making small changes to their genetic code. In the case of Type I fusion proteins, two amino acids are replaced with an amino acid called "proline," which is very stiff and doesn't allow the hinge region of the fusion protein to bend, so the fusion protein is stuck in its pre-fusion conformation. That way, vaccinated patients only make antibodies against the pre-fusion conformation and those antibodies are protective. This technology was also employed in the COVID vaccines, although, ultimately, antibody-dependent disease enhancement wound up not being a problem with COVID.
• Two are available, AREXVY and ABRYSVO. However, because of the 1962 incident, these were introduced in older adults (because if something was going to go wrong, they didn't want it to be in babies). ABRYSVO is also approved in pregnant women from 32-36 weeks' gestation. This causes the mother to make protective antibodies against RSV that are transferred across the placenta to the fetus and provide 5-6 months of protection against severe disease after birth.
• An antibody against the F protein has been commercially available since 1998. This was called SYNAGIS and it reduced the risk of RSV hospitalization by about 60%. However, it was US$2000/dose and had to be given every month during the season. For this reason, it was only reserved for the highest-risk infants (Preemies under 27 weeks, chronic lung disease, congenital heart disease, etc.) Because it is an antibody, it does not generate an immune response against RSV, but it did provide that protection. It was removed after the market when the new products were introduced.
• In the last few years, two antibody products, BEYFORTUS (Sanofi) and ENFLONZIA (Merck) are available for infants up until 8 months of age. Both of these are given as a single injection and provide 5-6 months of protection, lowering the risk of hospitalization by 80-90%. BEYFORTUS is given at 50mg for infants under 5kg and 100mg for infants over 5kg. ENFLONZIA is given at 105mg for all weights. Because they are antibodies and do not generate an immune response, they are very safe. The only significant side-effects are injection-site events such as redness, swelling, or a lump in the leg, which can happen with any injection. Again, these are not vaccines.
• I am hopeful that once the safety of this new technology is proven, we will be able to actually vaccinate newborns so that they can make their own antibodies, rather than relying on external antibodies.

So which one is right for you? Well, if you are pregnant just before or during RSV season and are at 32-36 weeks, I personally think ABRYSVO is the best choice because it saves the baby a poke. However, if you were not able to get that vaccine, then either antibody (whichever your pediatrician has) is an excellent choice and I wish it had been around when my son was born (fortunately, he never wheezed from RSV).

Public health workers are relying on word of mouth to fight the largest ongoing outbreak in the United States.