Bivalent vaccines and how they will help end the pandemic

CLINICAL MATTERS

The unprecedented rapid development of Covid-19 vaccines as well as their widespread deployment has saved more than 20 million lives. Vaccines have enabled the world to move beyond a pandemic mindset and have made it possible to safely resume most pre-pandemic activities. If that is the case and the World Health Organization (WHO) is already talking about the end of the pandemic, why will we even need updated vaccines? Are not the current vaccines enough to move on?

While there have been many vaccine platforms developed against Covid-19, the undisputed star of the show has been mRNA vaccines. The mRNA vaccines are a new and novel platform for inducing immunity against SARS-CoV-2. These vaccines have been a sort of “holy grail” for many vaccine developers. Once a methodology was shown to work, Moderna produced a candidate mRNA vaccine within 42 days of the identification of a genetic sequence for the spike protein. The most recent updated vaccines were also produced quickly, since this only entailed modifying the mRNA sequence.

The messenger RNA, which is what mRNA stands for, is the intermediate molecule between DNA and proteins for most living things. Our body utilizes mRNA to preserve the integrity of our DNA by ensuring that DNA stays in the cell nucleus and is not damaged by external factors. Depending on what is needed, mRNA is transcribed from the DNA sequence of a gene coding for a protein. It then travels outside the nucleus and is translated into the target protein at factories called ribosomes in the cytoplasm. The finished protein is then used for its intended purpose, which can range from structural proteins to enzymes to antibodies. Since proteins are much more cumbersome to synthesize and purify than mRNA, the concept of an mRNA vaccine to code for proteins that induce antibodies against specific antigens has been a goal of scientists for decades.

There are many technical difficulties, however, in producing an mRNA vaccine. Outside the cell, mRNA is very fragile. It can be destroyed by enzymes and environmental factors. Unmodified mRNA is recognized as a potential foreign virus by the body and an immune response can be triggered against it, leading to unwanted side effects. Once the mRNA gets into the cell, it has to get to the ribosomes and be transcribed in high enough amounts in order to elicit the appropriate immune reaction. This is where Moderna and subsequently Pfizer were able to take it to the next level. Both drug companies used lipid nanoparticles to protect the mRNA outside the cell and facilitate its entry through the cell membrane and into the cytoplasm. The mRNA was chemically modified to make it look like the body’s own mRNA. Once the lipid nanoparticles bring the mRNA inside the cell, biological signatures attached to the mRNA sequence guide it to the ribosomes to express the needed protein.

In the case of both Moderna and Pfizer vaccines, the protein encoded by the mRNA is a portion (S2 subunit) of the spike protein of SARS-CoV-2 that is responsible for viral entry into the cell. Once the target cell starts making enough copies of the S2 subunit, the body reacts to this foreign protein by making antibodies and T-cells. Because the foreign proteins are produced in the body’s own cells, the body thinks these cells are infected and proceeds to mount a robust immune response. This immune activation also generates memory B-cells and memory T-cells, which are long-lived and can quickly ramp up the immune response when exposed to the actual virus in the future.

Despite many technological hurdles, the first two mRNA vaccines were found to be highly effective in clinical trials. Efficacy rates were greater than 90 percent for preventing infection with the original SARS-CoV-2 viruses. Unfortunately, the propensity of SARS-CoV-2 to generate variants eventually decreased the original vaccine’s efficacy against infection due to increasing antibody mismatches on the spike protein. Because of the generation of a robust T-cell response on top of the antibody production, however, protection against severe disease remained. Boosters restored some protection against infection, but this was relatively short-lived and did not reach the initial level of efficacy against the original virus. Mixing mRNA vaccines with other vaccine types, termed heterologous boosting, also seemed to improve coverage against new variants of concern. While repeated boosting with the same old vaccine type did restore some efficacy especially in vulnerable populations, there was a ceiling to this strategy as variants of concern with increasing breakthrough potential arose.

In order to address the waning efficacy of mRNA vaccines against infection, manufacturers began to modify their vaccines. The beauty of mRNA vaccines is that it is relatively simple to modify the sequences for the target protein to that of the most recent variants of concern. Two strategies for updated vaccines were undertaken. The first uses a completely new virus sequence to replace the original virus sequence using the same quantity of mRNA. The second strategy uses half the quantity of mRNA of the original virus sequence along with another half mRNA quantity of the modified sequence. This latter formulation is known as a bivalent vaccine. For instance, the amount of mRNA in the original Moderna vaccine for boosting is 50 mcg. The updated bivalent vaccine has 25 mcg of the original Wuhan strain plus 25 mcg of the variant of concern. The same is true for the Pfizer vaccine except that the original booster dose is 30 mcg while the proportion of the original virus in the bivalent vaccine is 15 mcg and another 15 mcg for the variant of concern. The US CDC has updated their recommendation to simplify the administration of these updated vaccines. For those 12 years and above, the primary series (first two doses) should consist of the old (monovalent) vaccine, followed by one bivalent booster. They have completely gotten rid of the second booster since the bivalent booster is expected to work much better than two old boosters. For anyone who has already been given at least one monovalent booster, one bivalent booster can be given two months after the last booster. It remains to be seen whether these will be the same parameters in the Philippines, and we will have some time to observe the effect on the US population while we wait for the bivalent vaccines to arrive.

Preclinical data looking at neutralization titers of these new bivalent vaccines as boosters against variants of concern show much higher antibody activity compared to the original vaccine formulations. This was the basis of the FDA approval for bivalent vaccines and the process is consistent with what has been done for updated influenza vaccines. It remains to be seen whether higher neutralization titers will translate to actual infections prevented but there is reason to be hopeful. These updated vaccines are expected to temper the expected rise in cases over the winter months in the US, where people spend more time indoors. The emergence of new Omicron variants like BA.2.75 and the recombinant XBB, which is now causing a rise in cases in Singapore, make boosting with these updated vaccines more crucial. If the updated vaccine boosters effectively neutralize these new threats, the end of the pandemic will truly be in sight.