Monday, March 27, 2023
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Associate Professor of Medicine
Emory University School of Medicine
Atlanta, Georgia
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Emory University School of Medicine
Atlanta, Georgia
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Medscape: Colleen Kelley, MD, MPH, Associate Professor of Medicine, Division of Infectious Disease, School of Medicine, Emory University, recently joined us to discuss the current landscape of SARS-CoV-2 vaccines.
What are the different technologies for the currently available and emerging vaccines in the United States?
Colleen F. Kelley, MD, MPH: There are now 4 different vaccines available to combat COVID-19 in the United States: an adenovirus vector vaccine, Ad26.COV2.S; 2 messenger RNA (mRNA) vaccines, BNT162b2 and mRNA-1273; and a recombinant protein vaccine, NVX-CoV2373.[1-4] All are delivered intramuscularly.[1-4]
The adenovirus vector vaccine, Ad26.COV2.S, is available under Emergency Use Authorization (EUA) and is delivered by a single
initial dose followed by a booster.
[1] This vaccine delivers a replication-incompetent adenovirus vector with the genetic code for the full-length SARS-CoV-2 spike
protein inserted directly into a cell, inducing an immune response that produces spike protein-specific antigens.[5] Ad26.COV2.S is less preferred for use due to potentially serious side effects and should only be used in limited circumstances,
such as lack of availability of another SARS-CoV-2 vaccine.[1]
The 2 FDA-approved mRNA vaccines, BNT162b2 and mRNA-1273, are the most widely used and widely available SARS-CoV-2 vaccines in the United States.[6] Though these are the first-ever FDA-approved mRNA vaccines, the technology has been in development since the early 1990s.[7] Both vaccines use proprietary lipid nanoparticles (LNPs) containing mRNA, which is enveloped by cells and translated into a protein.[8] Both vaccines have an initial 2-dose regimen followed by booster doses.[2,3,7] For certain immunocompromised individuals over the age of 12, the FDA has issued EUA for third primary series doses of both mRNA vaccines.[2,3]
The recombinant protein vaccine, NVX-CoV2373, was recently granted EUA.[4] NVX-CoV2373 was created using a more traditional approach to vaccinology in which a laboratory-created recombinant protein induces an immune response by mimicking the viral spike protein.[9] The vaccine delivers the protein with the Matrix-M1 adjuvant to improve immunogenicity.[10] Like the mRNA vaccines, this vaccine involves a 2-dose vaccine series that will require boosting.[4]
Medscape: How effective are the vaccines for primary vaccination of adults?
Dr Kelley: All of these vaccines produce robust immune responses against the SARS-CoV-2 spike protein (Figure 1).[11] Early clinical trials showed high efficacy of Ad26.COV2.S (70%), BNT162b2 (95%), mRNA-1273 (94%), and NVX-CoV2373 (90%) against the ancestral viral strain.[5,8,9,12,13] All are also highly effective in preventing severe disease, hospitalization, and death.[1-4] However, the evolution of new variant strains of SARS-CoV-2 complicates things. The most recent data show that vaccine specificity against the virus really declines such that neutralization is lower for the newer variants than it was for the original ancestral strain.[ 14]
We know that a high level of antibodies is produced after vaccinations, particularly with the mRNA vaccine products, but we have also seen that these antibody levels tend to wane after a couple of months.[15,16] Waning of antibody levels is an important factor when we're thinking about efficacy and durability, or how long protections lasts, of these vaccines. Antibody neutralization decreases with time after delivery with all vaccines, especially in older people or those with underlying health conditions, providing the logic for boosting.[11,15]
Figure 1. Graphical Representation of the Immune Response of the Ad26.COV2.S, BNT162b2 and mRNA-1273, and NVX-CoV2373 Vaccines Against SARS-CoV-2[11]
Reprinted from Cell, 185(14), Zhang, Z., et al., Humoral and cellular immune memory to 4 COVID-19 vaccines, pp. 2434-2451.E17, Copyright (2022), with permission from Elsevier.
Medscape: Are there any safety issues with existing or newly authorized vaccines that clinicians should be aware of?
Dr Kelley: We probably have more detailed safety data on these vaccines than any other vaccines in history. The billions of doses[6] that have been delivered really show their exceptional safety profile and highlight how these amazing interventions have saved countless millions of lives over the last 2 years. With that said, anytime a patient gets a vaccine, they can certainly feel unwell for a few days. They may have local muscle aches, fatigue, or maybe even a low-grade fever or headache.[1-4] All of that is to be expected and not a safety concern.
Currently, the mRNA vaccines are both preferred for most populations due to their superior safety profiles and high efficacy, although they do seem to have moderate incidence of mild adverse effects.[2,3] The most significant safety issues with BNT162b2 and mRNA-1273 have been myocarditis and pericarditis among young men.[2,3] A small number of individuals developed Bell palsy following vaccination with mRNA-1273.[3]
Ad26.COV2.S has been associated Guillain-Barre and capillary leak syndrome in some extremely rare instances.[1] The vaccine also carries a low but non-zero risk of vaccine-associated thrombocytopenia and clotting that mostly affects young women, which led to the recommendations that this vaccine should only be used in limited circumstances.[1] However, it is preferable to use the Ad26.COV2.S vaccine over no vaccination.
NVX-CoV2373 is different because we know comparatively little about its efficacy compared to the other products, particularly against more recent viral variants such as the Delta and Omicron variants. As we saw with the other vaccines, some rare safety concerns don't become evident until a vaccine is in widespread use. Because NVX-CoV2373 hasn't been widely used and subjected to safety tracking, we know less about the potential for rare side effects.[4] Clinical trials have recorded 1 instance each of pericarditis, myocarditis and Guillain-Barre syndrome.[4]
Medscape: Are there any populations for whom specific vaccines are or are not indicated?
Dr Kelley: Yes, there are a few populations for whom there are specific considerations in vaccine choice. People under 18, people with previous instances of thrombocytopenia, and pregnant people should all be vaccinated with BNT162b2 or mRNA-1273.[2,3] In fact, the Centers for Disease Control and Prevention (CDC) recommends that the Ad26.COV2.S vaccine only be used in limited circumstances due to clotting and thrombocytopenia risk.
Currently, BNT162b2 or mRNA-1273 are the only vaccines with EUA for individuals aged 6 months to 18 years.[2,3,6] The PREVENT-19 clinical trial, which tested safety and efficacy of NVX-CoV2373 in individuals over 18 years, has been expanded to ages 12 to 18 years, but those results are not yet available as of August 2022.[9] Ad26.COV2.S is not recommended for use in people under 18.[1]
Ad26.COV2.S is also not recommended for use in pregnant people because of the risk of clotting and vaccine-induced thrombocytopenia.[1] The mRNA vaccines were shown to effectively generate maternal antibodies that transfer to newborns in the Division of Microbiology and Infectious Diseases (DMID) MOMI-VAX clinical trial.[17] NVX-CoV2373 has not yet been robustly tested in pregnancy, although data collection is ongoing.[4]
Medscape: What are the clinical implications of the different technologies in terms of public perception of their efficacy and safety? Could there be an effect on vaccine hesitancy?
Dr Kelley: mRNA vaccine technology has been in development for decades, but the mRNA vaccines against SARS-CoV-2 are the first to be made available by the FDA.[18] As a result, some subsets of the public have developed a high degree of vaccine skepticism towards BNT162b2 and mRNA-1273.[18] Some fear the vaccines were developed too rapidly for adequate safety testing. There are also a variety of conspiracy theories surrounding COVID-19 vaccines in general.
There is some hope for reduced vaccine hesitancy with the approval of the NVX-CoV2373 because, as a protein-based vaccine, it has a more traditional approach to immunogen design.[19] People who were hesitant to try the mRNA vaccines or the adenovirus vector vaccine, which are both newer vaccine platforms, might be more willing to accept a vaccine platform with a longer safety record.
Personally, I don't think that NVX-CoV2373 is likely to have a huge impact on vaccine hesitancy, because my sense is that the people who are holding out at this point are relatively committed to their decision. Additionally, I suspect that there are exceedingly low numbers of people receiving primary vaccinations these days (Figure 2). We do need to prioritize education for those who have been vaccinated but not yet boosted so that they understand the importance of boosting.
Figure 2. Data on Individuals Receiving the First Dose of a Vaccine Against SARS-CoV-2 by Date of First Injection[20]
Medscape: What do the data show about the efficacy of the vaccines for homologous booster vaccination of adults?
Dr Kelley: With respect to severe disease and hospitalization, boosting works. It is necessary. The data very clearly show the benefits of third and fourth boosters of the mRNA vaccines in people over age 50 and in immunocompromised individuals.[20] As with primary vaccination, the vaccine booster shots are less effective against new strains, especially Omicron (Table 1).[14,21] Most people in the United States have had SARS-CoV-2 infections,[22] and many of those people have had SARS-CoV-2 infection plus vaccine, conferring hybrid immunity. This combination appears to confer robust immunity.[16]
The FDA has recommended that pharmaceutical companies shift to Omicron-specific vaccine immunogens as early as fall 2022.[23] I recommend a third dose for all people. For people who are advanced in age or have significant comorbidities, I recommend moving forward with the fourth COVID vaccine dose, which is now available as a bivalent mRNA booster that adds Omicron BA.4 and BA.5 spike protein components to the current vaccine composition.[24]
Table 1. Vaccine Efficacy Projections (July 2022)
|
|
Effectiveness at Preventing |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
Ancestral |
Alpha |
Beta |
Gamma |
Delta |
Omicron |
||||||
|
Vaccine |
Severe Disease |
Infection |
Severe Disease |
Infection |
Severe Disease |
Infection |
Severe Disease |
Infection |
Severe Disease |
Infection |
Severe Disease |
Infection |
|
Ad26.COV2.S |
86% |
72% |
86% |
72% |
76% |
64% |
76% |
64% |
76% |
64% |
57% |
33% |
|
BNT162b2 |
95% |
86% |
95% |
86% |
95% |
84% |
95% |
84% |
95% |
84% |
72% |
44% |
|
mRNA-1273 |
97% |
92% |
97% |
92% |
97% |
91% |
97% |
91% |
97% |
91% |
73% |
48% |
|
NVX-CoV2373 |
89% |
83% |
89% |
83% |
86% |
82% |
86% |
82% |
86% |
82% |
65% |
43% |
Institute for Health Metrics and Evaluation estimates from a model run for the United States on July 15, 2022, on data up to July 13, 2022. This iteration of the model assumes that 80% of individuals who received a first booster dose will receive a second booster 4 to 6 months later.[14]
Medscape: Can the vaccines be used in mix-and-match boosting protocols?
Dr Kelley: The data certainly show that mixing and matching amongst vaccines is safe and can improve immunogenicity; whether it is ultimately beneficial remains to be seen.[25] The National Institutes of Health (NIH) COVAIL trial is ongoing to assess the level of protection offered by different combinations.[26] In the United Kingdom, the Com-COV2 trial is testing mix-and-match boosting efficacy with the BNT162b2, mRNA-1273, and NVX-CoV2373 vaccines, as well as ChAdOx1 nCoV-2019, which is not yet authorized for use in the United States.[25]
The FDA has approved heterologous boosting, or mix-and-match boosting, for all 4 of the vaccines currently available in the United States.[1-4] Importantly, primary vaccination series should involve the same vaccine before heterologous boosting is considered: prime-boosting, as this method is called, shows good efficacy.[24] In most situations, heterologous primary series have not yet been authorized; however, mixed mRNA primary series are allowed if the identity of the patient's initial dose is unknown or a second same-type vaccine is unavailable[27] Mix-and-match boosting may prove useful in improving boosting timelines when supply chain and distribution issues make homologous boosting impossible.[25]
Medscape: What are the differences among the vaccines in terms of distribution and administration?
Dr Kelley: The cold chain issues and distribution issues associated with the mRNA vaccines, which have extremely low temperature requirements,[2,3] have been worked out quite well, and most providers have adjusted to accommodate what they need in their clinic spaces for the mRNA vaccines. This is particularly true in the United States, although other places across the globe, especially in the Global South, may still be having issues related to vaccine distribution infrastructure.
Another hurdle in distribution is the ability to update vaccine immunogens quickly to match the new variants circulating. The mRNA vaccines can be produced quickly and are much easier to modify than the other platforms.[7] Creating an Omicron-specific vaccine is fairly straightforward and can be completed relatively quickly for the mRNA vaccines. However, certain geographic areas may run into distribution issues, especially with the mRNA vaccines, and the updated vaccine may not be delivered until a new variant has already spread widely. We could end up "chasing our (variant) tails."
Storage requirements are easier for Ad26.COV2.S and NVX-CoV2373, which both require only standard refrigeration.[1,4] However, vaccine development is slower: while distribution may have fewer restrictions, there is still the potential for a significant time lag between the emergence of a new variant and the delivery of a booster capable of combatting it.[18] These trade-offs are becoming increasingly important as it becomes clear that COVID-19 is not going away in the near future.
Medscape: What are the potential clinical implications of these differences for use in different global regions?
Dr Kelley: There are definitely trade-offs that public health officials will need to weigh: mRNA vaccines, while extremely effective, require special storage equipment that may not be available in countries with fewer resources or less-developed healthcare infrastructure.[7] Ad26.COV2.S, while less effective, requires only 1 dose for primary vaccination and has less stringent storage requirements.[1] NVX-CoV2373 requires 2 doses but only needs standard refrigeration, making it more logistically feasible for global access.[4,7] Stark disparities exist in global access to COVID vaccines: as of May 2022, only 15.7% of eligible people in low-income countries have received a single vaccine dose.[28] Tremendous global effort is needed to combat these inequities.
Medscape: What key takeaways would you like providers to have regarding existing and emerging vaccines against SARS-CoV-2?
Dr Kelley: Providers need to stay abreast of data on circulating variant strains, transmission rates in their geographic area, and recommendations about vaccines and boosters, as well as ongoing treatment guidance. I also want to touch on the potential for post-acute COVID syndrome (PACS), commonly called long COVID, in some patients -- studies now support the existence of serious, long-term impacts on patient quality of life.[29] Vaccination and immunity from prior infections both reduce the risk of long COVID, and initial data suggest that the effect might be quite significant. That protection alone is a good reason to remind people to stay up to date on their vaccines, even though evidence suggests that transmissibility is increasing while pathogenicity is decreasing with each spike in infections.[30] In other words, hospitalizations and deaths are going down in proportion to the increasing numbers of cases, but we will still expect to see morbidity and mortality from COVID, as well as ongoing morbidity from long COVID.
The onslaught of new technology, changing data, and the changing recommendations has been a significant challenge for providers during this pandemic, but we have made a difference. Every vaccine dose we deliver helps strengthen population-level immunity. The medical community is currently watching SaRS-CoV-2 transition from an exceptionally devastating and deadly virus for many people into something some experts project will be more akin to common coronaviruses or rhinoviruses in the future. However, we are not there yet: COVID-19 is still a serious and potentially fatal illness, and providers need to remain vigilant.
This transcript has been edited for style and clarity.
