COVID-19 has emerged to be the most challenging pandemic faced in the 21st century. With total cases as of April 2021 at about 147 million worldwide and 32 million in the US, this virus has demanded our attention since 2019. International efforts have shifted from limiting the spread of the virus to developing treatment and vaccination beyond prevention. This review is a snapshot of the constantly evolving field of COVID vaccines.
Vaccine development against SARS-CoV and MERS-CoV have been in the development stages for several years, but only with the current pandemic have gone beyond preclinical testing. Traditional vaccines have used inactivated, live-attenuated, killed, and subunit vehicles to stimulate an immune response. Two of the three FDA granted emergency use authorization COVID-19 vaccines are novel due to their use of mRNA. While not new, these are the first mRNA vaccines to be approved and used in human trials. Put simply, mRNA vaccines provide our immune cells the blueprints to recognize the spike protein portion of the coronavirus. Additional vaccines like the one offered by Johnson and Johnson, utilize a non-infectious form of another virus (adenovirus) as a transport for DNA instructions for our cells to make spike proteins. Once the spike proteins are on the outer membrane of the cell, the immune system can then form antibodies against them.
Efficacy of the Current Leading Vaccines Worldwide
In the United States, Moderna and Pfizer were the first to earn emergency authorization and are responsible for immunizing over 221 million Americans as of April 26, 2021(majority of these are single dose numbers to date). The COVE study enrolled 30,240 participants split equally in the vaccine and placebo arm. The data showed Moderna to be 94% effective in preventing new cases with none of the fully vaccinated group experiencing a severe COVID infection. Pfizer’s initial study enrolled 43,448 participants, 21,720 with vaccine and 21,728 with placebo. The Pfizer study showed nearly identical efficacy of 95% with two doses and the additional findings of 52% efficacy after the first dose. Since these initial studies, more current data has shown improved first dose efficacy between 65-72% for Pfizer, encouraging Americans to focus on receiving at least one dose as soon as possible. This updated data comes from the SIREN study, which has the added benefit of having studied Pfizer in the UK where B.1.1.7 variant was most active and has since become active in the US as well as Brazil.
After the initial wave of FDA approved vaccines, additional methods utilizing an adenovirus vector have emerged from AstraZeneca (AZ) and Johnson & Johnson (J&J). Current data involving 11,636 participants shows the Oxford vaccine (from AZ) has a single dose efficacy at approximately 62%, with 90% efficacy after the second dose. In February 2021, J&J received emergency authorization from the FDA after preventing 85% critical COVID cases in a 40,000-patient double blind, randomized trial after just one dose.
Additional contributions to the vaccination efforts include Russia’s Sputnik V, China’s CoronaVac, and the American-developed but foreign-tested Novavax. With a mechanism identical to the J&J vaccine, the Sputnik V has boasted an efficacy of 91.6% from an early phase 3 RCT analysis thus far. Utilizing an inactivated form of the SARS-CoV-2 virus, the CoronaVac has shown promising immunogenicity in early phase trials with ongoing Phase 3 trials. With varying efficacy between 60-90% from international trials in the UK and South Africa, America’s Novavax may show more promise against the emerging variants of the virus. Novavax’s more recent claims of 96% efficacy have yet to be reviewed sufficiently but certainly show the promise of global efforts for ongoing vaccine research.
While the exact titers and assays correlating with this vaccine’s efficacy are still being determined, early trials have shown immune responses in patients well beyond 6 months. Titers and assays help us to assess our current antibody reserve against a specific pathogen such as titers sometimes required by schools for Hepatitis viruses or Varicella (Chicken Pox). So while the vaccine shows consistent antibody reserve over 6 months, infection with one of the COVID variants has resulted in more scattered immunity findings ranging from months to over a year. The data suggests the Coronavirus vaccines offer more consistent protection than convalescent antibodies from past infection and they offer protection against other variants of this mutating virus. According to a 2020 study of Boston-area COVID healers, or those recovered from an infection, the magnitude of IgG or antibody response and duration were inconsistent. Those with more severe infections requiring hospitalization or aggressive treatment had longer lasting and greater magnitude immunity compared to those who were less or even asymptomatic. Therefore, the vaccines show promise for long term immunity without the risk of requiring a bout of severe disease. Based on these findings and the virus’s propensity for mutation, it is possible for at least the next few seasons that boosters or annual COVID vaccinations will be offered.
Safety and Ongoing Trials
Besides the predominant vaccines offered today worldwide, there are an additional 60+ in development that show promise as they undergo repeated trials. The US Government’s Operation Warp Speed substantially funds the ongoing efforts of a handful of companies including those who have produced the Moderna, Novavax, and Oxford vaccines. The largest global organization of and for those involved with the regulation of healthcare, The Regulatory Affairs Professional Society (RAPS), tracks the progress of the authorized and in-progress vaccines. Currently, RAPS reports 13 approved vaccines worldwide and an additional 56 that are between Preclinical and Phase 3 of trials.
There has been much discussion regarding potential side effects and reactions from the COVID-19 vaccine, as an mRNA vaccine in humans is somewhat uncharted territory. Most recorded reactions have been mild to moderate, including local injection site irritation with systemic reactions noted up to 7 days post-vaccination. Systemic symptoms included reports of fatigue, headache, muscle pain, fever, nausea, and lymphadenopathy. Of note, most systemic reactions were reported after receiving the second dose. These systemic symptoms were recorded to be more severe and occurred with a higher frequency in patients below 55 years of age as compared to those above 55 years of age. Despite reports of systemic reactions lasting for 7 days, most recipients reported resolution of their symptoms within an average of one day. While there have been reports of life-threatening allergic reactions such as anaphylaxis, the rate of anaphylaxis post-vaccination has been 2-5 people per million in the US. Vaccine Adverse Event Reporting System (VAERS) has reported 2,794 reports of death post-vaccination (0.00167%). However, there is no evidence of the vaccine contributing to the reported deaths at this point in time or any data showing this rate of deaths is different from the baseline rate of death in any given population. Important to note, anyone can report events to VAERS and the database contains unverified information. For other conditions historically associated with vaccines, including Guillain Barre Syndrome (GBS), the evidence is overwhelmingly positive. Zero cases of GBS have been reported following the mRNA vaccinations to date.
On April 13th, the availability of the J&J vaccine was interrupted due to a report of 6 patients who experienced blood clots out of nearly 7 million recipients. The headlines contributed to public hysteria and skepticism while the numbers are less concerning; that being said, the cerebral venous thrombi found in these women under 55 years of age were cause for concern due to the rarity of this particular clot. J&J also harked back on their past research and safety findings which closely match those of the other vaccines offered. Similarly over the past few weeks, AZ has had to defend their vaccine’s safety for concerns of increased frequency of clots and decreased number of platelets. The European Medicines Agency (as this vaccine was mostly halted in European countries) scrutinized the data and found no direct causal link between the vaccine and the coagulopathies. As research continues on the vaccines, of course part of this progressive work is on safety and risk avoidance. At this point on a global scale, the vaccines available have been proven safe and with benefits far outweighing the risk of long-term sequelae stemming from COVID infection. To highlight this, it is noted that approximately 1 in a million women died from the Johnson and Johnson vaccine. When you look at women within the same age range as an equal comparison, approximately 125 women died from COVID-19. So, take the vaccine and have 1 in a million chance of death or don’t and have a 125 times increased chance of dying from the disease.
The Advisory Committee on Immunization Practices (ACIP) has recommended that the potential benefits of the COVID-19 vaccine outweigh the risks of adverse vaccine effects, particularly when compared to outcomes of being infected with COVID-19. However, it would be remiss not to mention that there are still many unknown variables both with COVID infection and vaccination. Large-scale vaccination efforts have been underway for too short a time period to fully understand the long-term efficacy of immunization. Establishing recommendations for vaccinating those 16 years and older with the Pfizer vaccine has been established through the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Using this measure the Pfizer vaccine had a high certainty for preventing symptomatic disease. However, the same assessment had a low certainty in its estimates of death prevention. Studies are ongoing to determine how long antibodies persist, and currently available evidence suggests that antibodies may be present beyond 6 months. As such, it is prudent to maintain social distancing practices and vigilance until more evidence and data is collected.
Throughout the pandemic there has been skepticism about everything from the virus outbreak origin story to the vaccine safety. The Unbiased Science Podcast has outlined some of the most common questions, myths, and misconceptions that have arisen. As with other vaccines, there is the misconception that people can get COVID from the injection–although there is no live virus in any of the vaccines offered. One of the primary concerns has been the speed of the vaccine development, which has raised questions about its safety as it appeared “rushed”. The truth is that the severity of the pandemic mobilized international resources to find answers in a more immediate time frame but no clinically necessary steps were skipped in testing or development. Media coverage of the mRNA vaccines has depicted this method of vaccination as “uncharted territory”, though this research has been ongoing for more than thirty years. As the general population heard more about mRNA vaccines, more myths arose including that they were capable of altering DNA, harming unborn children, causing infertility, and consisted of dangerous chemicals. There is no interaction between mRNA and the DNA of the person receiving the vaccination and it has shown no effect on fertility. As aforementioned, current studies are showing encouraging safety in pregnant women. Finally, the ingredients to each vaccine are publicly available and have been tested for safety prior to human trials. Any question of safety–no matter how small, halts the process and in-depth investigation ensues to ensure safety before the vaccine continues rolling out. In an era of increased media distrust and widespread publication of misinformation across the internet, it is important to critically evaluate the source for each claim about these vaccines.
Vaccines in Specific Populations
As of March 2021, Pfizer and Moderna have begun pediatric COVID vaccine trials with babies and children aged 6 months to 11 years old. While we do not have enough information about trial results, we do know how vaccines will be developed in comparison to the adult-form vaccines. Both companies are initially studying lower doses before moving on to a second stage to evaluate long-term effectiveness and safety. Meanwhile, both companies are continuing their adult vaccination data collection and adolescent-specific studies, such as Moderna’s TeenCOVE for 12-17 year-olds. The National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority have also partnered with these companies to ensure the safety of these vaccines in the pediatric population.
COVID vaccination in pregnant patients remains a somewhat controversial subject due to limited information and active trials. This has been complicated by pregnant patients being excluded from the first phase 3 trials. However, pregnancy is not a contraindication to receive the vaccine. The impact of the COVID virus itself on pregnancy is not also not well-known, however pregnant patients had a higher likelihood of having a more severe infection and there have been several pregnancy complications associated with the virus. Specifically, thrombosis and premature fetal membrane rupture have been reported in pregnant patients with the virus. There is evidence that both supports and refutes vertical transmission of the virus to the fetus and requires further research. Adverse reactions to the vaccine specific to pregnant patients have not been reported, and humoral immunity post-vaccination was the same between pregnant and non-pregnant patients, suggesting the vaccine has equal efficacy in pregnant patients. Additionally, vaccine side effects occurred with the same frequency and severity in pregnant and non-pregnant patients. The American College of Obstetrics and Gynecology has issued a statement that vaccines should be made available to pregnant and lactating patients, and discussions of whether a patient should receive the vaccine are left to the patient and their physician. Furthermore, preliminary results from a study by Dr. Shimabukuro et al. of 3,958 pregnant women show that mRNA COVID vaccines are generally safe with adverse outcome rates nearly identical to those in the general population.
The discussion of whether children should be vaccinated against COVID-19 is complicated by a lack of clinical trials in the pediatric population. Currently only the Pfizer mRNA has been expanded to include children between 12-17 years old. Compared to adults, the incidence and mortality burden of COVID-19 in children is significantly lower. The most recent data reported by the American Academy of Pediatrics has shown that children make up 13.6% of COVID cases in the United States. Hospitalizations and fatalities due to COVID were also significantly lower in the pediatric population, with 0.1-1.9% of children testing positive requiring hospitalization and 0.03% COVID-related deaths. Data regarding the role of children in transmission of the virus is limited due to early nationwide school closures. Children with comorbidities such as metabolic disorders face a higher risk of infection and complications from the virus, just like their adult counterparts. While otherwise healthy children may be at less risk at developing symptomatic disease and having more serious complications, the impact of the virus on social development and education cannot be underestimated. The social and economic burden of closing schools and the downstream psychological effects on school-aged children is an important consideration in approaching pediatric vaccination.
Much like the pediatric and pregnant populations, specific safety studies have not yet been completed or reported on from the immunosuppressed population. That being said, many with varying diagnoses of immunosuppression have already undergone vaccination without significant consequence (SOURCE). For example, those with low CD4 T-cell counts with a diagnosis of HIV were included in early safety and efficacy studies but their specific outcomes were not extrapolated from the sample. Further, there are ongoing clinical trials for nearly every pre-existing immune system disease process that can be found on the clinicaltrials.gov website.
New Variants of SARS-CoV-2 and Vaccine Efficacy
As early as December 2020, new variants of the virus have been found throughout the globe and currently the CDC is monitoring 5 total variants of concern. The virus continues to mutate its S gene coding for different spike protein configurations creating new variants and some will inherently carry greater threat but vaccine efforts are already underway in response. Pfizer is still compiling data but has already shown possible cross-immunity from their initial vaccine with the variants seen from Brazil, South Africa, and most recently, California. Moderna’s vaccination indicated continued efficacy against strains that attacked New York and the UK but showed a drop-off in titers effective against the South Africa variant. We also know the mRNA vaccines are more effective against variants than adenovirus vaccines such as AstraZeneca or J&J. Viral replication is what allows for continuous spike protein mutation not unlike our yearly battle with Influenza variants, which brings up the possibility of seasonal COVID vaccine updates. Finally, recent studies on the virus’s pathophysiology indicate greater involvement of T cells than previously considered, which may shape the next wave of vaccines as they target the virus in more ways than just solely by its spike protein.
There is undeniable excitement after achieving full vaccination as many people hope to return to their normal social activities without restriction. As of April 2021 the CDC’s recommendations relaxed substantially allowing a return to indoor dining between smaller groups of fully vaccinated people. An added benefit of vaccination is that quarantining after a likely exposure is no longer required or suggested unless the person experiences related symptoms. Travel has slowly begun to open up internationally but, domestically, a fully vaccinated person need only wear a mask to return to the pre-COVID era of flying. Studies conducted by multiple international governing and regulating bodies have found these vaccines to be safe and efficacious. The data and updates on this topic are promising and at this time vaccination is recommended for most people, with the hopes that we can bring an end to the greatest pandemic we have seen in this century.
I am vaccinated, what are the recommendations for me now?
As of April 2021, CDC guidelines consider individuals fully vaccinated after 2 weeks have elapsed following the second Pfizer or Moderna vaccine or after the single dose of the Johnson and Johnson vaccine. The effectiveness of both Moderna and Pfizer at preventing COVID-19 infection and symptomatic illness in the United States is currently at 90%. However, data on protection against asymptomatic transmission and infection showed only an 80% effectiveness. During this same time, the CDC received reports of breakthrough infections from 46 U.S states and territories. A breakthrough infection is a defined as a person who has SARS-CoV-2 RNA or antigen detected greater than 14 days after completing the primary series of an FDA-approved COVID-19 vaccine. There was a total of 9,245 breakthrough infections reported as of April 26, 2021. 9% of these cases resulted in hospitalizations and 1% resulted in death, although it is important to note that a number of these cases were not related to COVID-19 (29% of hospitalizations and 15% of deaths).
Therefore, recommendations surrounding those considered fully vaccinated still requires the use of masks and social distancing in public and large gatherings where the immunity status of all in attendance is unknown. Fully vaccinated and immunocompetent unvaccinated individuals are considered safe to gather with each other without the use of masks or social distancing. At the same time, caution should be exercised when visiting others that are at risk of severe COVID infection and mask wearing with social distancing should be exercised when interacting with immunocompromised and elderly individuals. Additional CDC guidelines state that quarantining following an exposure is unnecessary if the appropriate timeline of the respective vaccinations has been reached. These recommendations are leading some states, such as New York, to lift quarantine restrictions for out of state visitors that have documented proof of vaccination.
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Josh Bridge, MSIII
Sarah Rokhlin, MSII
Aaron Wolfe, DO, FACEP