Stuart R. Gallant, MD, PhD
Back in April, PharmaTopo posted on lipid nanoparticle formulations for Covid-19 vaccines [1]. Because the Moderna bivalent vaccine recently arrived in clinics, I thought it would be nice to look at what makes the bivalent booster special.
Covid 19 Infection
Before discussing the vaccine booster, a quick review of Covid-19 infection…. The figure below presents an exterior view of a Covid-19 virion. The individual Coronavirus elements are depicted in separate colors: blue for the viral envelope, red for the envelope proteins, green for the membrane proteins. The spike protein is shown in turquoise, and glycan in shown in orange.
The spike protein is tremendously important in the process of infection. Spike exists on the virion surface as a pear-shaped trimer with the S1 subunit pointed out and the S2 subunit anchored in the viral envelope. S1 interacts with angiotensin-converting enzyme 2 (ACE2) on the surface of human cells, allowing the virus to gain entry by endocytosis, leading to viral replication and amplification of the infection in the patient. ACE2 is displayed in the microvasculature of numerous tissues of the body (especially lung, fat, and brain, but also liver, kidney, and heart) [2, 3], though the virus seems to be particularly drawn to nose, throat, and upper airways of the lungs as the site of initial infection.
Usually, the patient clears the infection and return to their normal activities; however, for some patients, the infection leads to worsening symptoms. The following graph illustrates some key features of the symptom, measured values over time, and test results during infection of a presumably Covid 19 naïve patient [3]:
The following observations can be made from this figure:
- Symptoms: Some patients may not notice any symptoms during the course of their Covid-19 infection. However, around 5 days after infection, many patients may develop mild symptoms (fever, malaise, cough, headache, and diarrhea). Some progress to shortness of breath, and a few require hospitalization.
- Defenses: Humans have a 4-fold defense against viral infection: 1) anatomical barriers (skin, mucous) defeat many viruses, 2) intrinsic immunity (this layer is relevant to retroviruses, rather than Coronaviruses), 3) the innate immune system includes the inflammatory response to viruses (leading to fever, malaise, and other systemic symptoms), as well as other responses, such as that by natural killer cells (which destroy virally infected cells), and 4) the adaptive immune system which includes response by T-cells and B-cells. The adaptive immune system takes longer to ramp up, only producing measurable amounts of antibodies at more than 14 days after infection.
- Dysfunction: Things can go sideways for some patients. Though measurable virus ceases to be isolated from the respiratory tract at a little more than 14 days after infection, some patients worsen clinically, displaying progressive hypoxia. The immune system, including macrophages and T cells, is responsible for this late pathology. Fortunately, as the causes of this clinical syndrome have become better understood, effective medical interventions have significantly improved the prognosis of these patients.
Moderna Bivalent Booster Formulation
One critical intervention to improve the course of Covid-19 infection has been vaccines of all types. The mRNA vaccines from Moderna and Pfizer/BioNTech have captured the popular imagination because of the relatively novelty of their technology, compared to some other methods of vaccine delivery, and because of their effectiveness [4].
In terms of formulation, the Moderna bivalent booster is similar to the original Moderna vaccine [1]. There is a minor tweak to the buffer composition without effect on product pH range of 7.0 to 8.0. The amount of lipids is cut in half—in proportion to the decrease in active ingredient from 100 micrograms to 50 micrograms total mRNA.
The active ingredients of the bivalent booster are 25 micrograms of the original Wuhan spike protein mRNA and 25 micrograms of the BA.4/BA.5 spike protein mRNA. Vaccination with the bivalent Moderna jab reinforces existing immunity to the original Covid-19 strain and adds immunity to the Omicron BA.4 and BA.5 strains currently circulating.
Spike Protein and Viral Escape from Immune Surveillance
Vaccination with an mRNA vaccine results in distribution of the active ingredients to predictable locations in the body: 68% of the mRNA remains at the injection site, 27% goes to local lymph nodes, 2% goes to more distant lymph nodes, and 2% goes to the spleen [5]. At each of these sites, some of the mRNA is taken into the patient’s cells and causes those cells to produce copies of the Covid-19 spike protein.
Spike was selected as the target of the initial round of vaccines from most vaccine makers for a boatload of reasons: 1) spike has a critical roll in binding to human cells, so inducing the expression of antibodies against spike could help limit Covid-19’s ability to infect cells, 2) during viral infection, segments of spike are displayed on the surface of infected cells, so enhancing the immune response against spike could aid in clearance of infected cells before they released a new crop of virions, 3) containing sequences that the human body recognizes as non-self, spike promotes a strong immune response from both B cells and T cells, and 4) because spike is important to viral binding to ACE2, there are limits to the ability of the virus to tolerate changes in the spike sequence (i.e., spike is fairly well conserved). By vaccinating with spike protein, the human immune system is primed to respond to a Covid-19 infection. Because the body is ready to produce large amounts of antibody early in the infection, the severity of the illness may be greatly diminished in vaccinated individuals.
However, over time new viral variants with subtle changes to spike have appeared. Covid-19 spike protein has a receptor binding domain (RBD) which interacts with ACE2. The RBD is a place that neutralizing antibodies bind to Covid-19 to limit the viral infection and clear virus from circulation. In early 2022, Ye and coworkers [6] reported that “the omicron spike has undergone extensive mutations in RBD regions where known neutralizing antibodies target, allowing the omicron variant to escape immune surveillance aimed at the original viral strain.”
Also, in early 2022, He, et al. [7] reported that the spike protein of SARS‐CoV‐2 Omicron (B.1.1.529) had a reduced ability to induce antibodies. The virus was exploring the possible space of spike sequences and finding mutations that preserved infectivity while decreasing immunogenicity.
More concerning was a study published a few months later in 2022 by Wang and coworkers [8]. In this study, variants BA.4/5 were exposed to sera from boosted patients and found to be substantially (4.2-fold) more resistant. This study raised the possibility that Coronavirus was in the process of evolving away from the protection offered by the first generation of Covid-19 vaccines, and it created an urgency for a new booster.
The Bivalent Approach and The Future of Vaccination
Having discussed the challenges of vaccinating against Covid-19, what can we understand of the future of vaccination to prevent this illness?
- Currently, the approach is to inoculate with a primary series of two jabs of the original vaccine (blue perimeter) which covers the original Covid-19 virus well and the BA.4/BA.5 variants less well. A bivalent booster (green perimeter) enhances immunity to cover the recent variants.
- Presumably, the primary series of the original vaccine will be shortly replaced with a primary series of the bivalent vaccine (for those who have not been vaccinated at all).
- It’s unclear how quickly Covid-19 will continue to change:
- Covid-19 may have shot its shot, and there may not be significant space for further mutation of spike. In that case, the bivalent vaccine may be sufficient for a considerable period of time.
- On the other hand, the pressure of evolution in response to the human immune system may lead to continued development of new Covid-19 variants. In that case, new vaccines may be required to cover the evolving population of variants [9].
- One interesting option is to attack two separate viral proteins (spike and another viral protein). Scientists are developing a vaccine that targets Covid-19 nucleocapsid protein, as well as spike, in the same vaccine [10]. The nucleocapsid protein is highly immunogenic, so it would be expected to generate strong antibody titers. Unfortunately, nucleocapsid protein is located entirely inside the virion. (It therefore cannot be seen on the exterior view of a Covid-19 virion shown above.) As a result, the nucleocapsid immune response would mark infected cells for death, but it would not neutralize virus in circulation in the body. Over time, the nucleocapsid protein might also vary in its structure in response to immune pressure. It remains to be seen if the two-protein approach offers advantages, compared to a laser-focus on spike.
In any case, creative new approaches to vaccine development can be expected if Covid-19 continues to evolve and present a problem for public health.
[1] pharmatopo.com/index.php/2022/04/03/lipid-nanoparticles-for-covid-19-vaccines/
[2] Letko, M., et al. “Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses,” Nature Microbiology 5, 562-569 (2020).
[3] Marik, P.E., et al. “A scoping review of the pathophysiology of COVID-19,” International Journal of Immunopathology and Pharmacology 35, 1–16 (2021).
[4] Booth, W. and Adam K. “Can I choose my covid vaccine? Strong opinions on Oxford vs. Pfizer emerge in U.K.,” Washington Post, February 21, 2021.
[5] Bahl, K., et al. “Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses,” Molecular Therapy Vol. 25, 1316-1327, June (2017).
[6] Ye, G. “Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain,” Nature Communications 13:1214 (2022).
[7] He, C., et al. “Spike protein of SARS‐CoV‐2 Omicron (B.1.1.529) variant has a reduced ability to induce the immune response,” Signal Transduction and Targeted Therapy 7:119 (2022).
[8] Wang, Q., et al. “Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5,” Nature 608, 603-608 (2022).
[9] Sun, L.H. “U.S. plans to shift to annual coronavirus shots, similar to flu vaccine,” Washington Post, September 6, 2022.
[10] Purtill, C. “Experimental COVID-19 vaccine could outsmart future coronavirus variants,” Los Angeles Times September 14, 2022
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