Vaccine Approval.

 The approval process for vaccines is arduous and involves the following steps:

1. Preclinical: Laboratory and animal testing to determine potential use in humans.
2. IND (Investigational New Drug) Application: Submission of R&D and preclinical data to the FDA for review and initiation of human trials.
3. Phase 1: Generally, a small trial conducted in 20-100 healthy people to determine safety, dosage, and immune response.
4. Phase 2: Mid-range trial conducted in several hundred people to assess dose-response and adverse events associated with the vaccine.
5. Phase 3: Large RCT (Randomized Controlled Trial) involving thousands of people to assess efficacy (does the vaccine work under ideal conditions?) and safety (does the vaccine cause harm?) versus a placebo.
6. BLA (Biologics Licensing Application): Comprehensive submission of all preclinical and clinical data to the FDA for review. There is no timeline for approval. In emergency situations like the COVID-19 pandemic, approval may be granted under an EUA (Emergency Use Authorization).
7. Phase 4: Post-approval oversight and ongoing monitoring that may require post-marketing studies to further assess known or potential serious risks. Vaccines are closely monitored using multiple surveillance systems including: VAERS (Vaccine Adverse Event Reporting System), BEST (Biologics Effectiveness and Safety) program, the FDA Sentinel Program, the FDA and CMS (Centers for Medicare & Medicaid Services) partnership program, the V-Safe phone app, and the CDC Vaccine Safety Datalink.

Approval of the Moderna, Pfizer, and Johnson & Johnson COVID-19 vaccines just a year after the first US cases represents an unprecedented achievement—the most amazing feat of science in my lifetime. Traditional pathways were accelerated by conducting them simultaneously rather than in sequence. For example, instead of waiting for approval before scaling up production, millions of doses were ready to go on day one. People receiving the vaccine are not “guinea pigs.” In fact, just the opposite—the guinea pigs are those choosing to avoid vaccination, willing to serve as “controls” in this great experiment being conducted by Mother Nature involving a deadly virus and a worldwide pandemic.

 

 

The Moderna and Pfizer Vaccines.

 Both the Pfizer (BNT162b2 mRNA COVID-19) and Moderna (mRNA-1272 SARS-CoV-2) vaccines work by delivering genetic material encoding for the COVID-19 spike protein to human cells where it is then translated and amplified. Viral RNA (ribonucleic acid) is unstable in the bloodstream, and requires packaging lest it dissolve before reaching its target. In the case of the Pfizer and Moderna vaccines, this means encasing the RNA within lipid nanoparticle transport vehicles. Once delivered to human cells, the RNA is amplified and translated to produce clones of the spike protein (but not the actual virus). Trimers of spike protein are then released into the bloodstream while the viral RNA is left behind to harmlessly degrade within the cell cytoplasm. Circulating spike proteins are immediately recognized as “foreign,” setting off the cascade of immunologic events (described in part 1) that culminate in active immunity against the virus. One of the advantages of the mRNA vaccines is that they directly stimulate T-cells, resulting in a robust cell-mediated immune response—a necessary feature in the fight against viruses. Both humoral (B-cell) and cell-mediated (T-cell) immunity occurs. The process is quite ingenious, a testament to the innovativeness of the human mind. It’s important to know that no living virus is used and that the viral RNA never makes its way into the nucleus of host cells, meaning that it cannot possibly be taken up into the human genome. The vaccines have been thoroughly vetted and are now in mass distribution.

 

 

The components of the vaccine are pretty straight forward: modified viral messenger RNA encoding for the COVID-19 spike protein, lipid nanoparticles comprised of miniscule amounts of cholesterol and three other lipids (fats), a few salts including simple table salt (sodium chloride, potassium chloride, sodium phosphate dihydrate, and potassium phosphate), and a dash of sucrose (table sugar). That’s it. There are no preservatives, thimerosal, artificial coloring, or vaccine adjuvants. Next, compare that to the ingredients in a bagel dog. Now that you know what’s in the vaccine, there is less to fear (although you should remain wary of hot dogs).

 

 

The phase 3 efficacy trials for both the Moderna and Pfizer vaccines yielded excellent results—far exceeding expectations and better than for many other common vaccines including the flu shot. Results for the Pfizer vaccine were published in the New England Journal of Medicine on December 31, 2020. In the trial, 21,720 volunteers received the BN162b2 mRNA vaccine while 21,728 controls received the placebo. Enrollees were aged 16 and older, and received two doses administered three weeks apart. Excluded from the trial were people with prior COVID-19 infection, pregnant women, immunocompromised individuals, and those receiving immunosuppressive therapy. The results were tabulated after 14 weeks  (although the study will continue  to monitor patients for two years). The primary endpoint was the number of patients developing symptoms of COVID-19 infection occurring at least seven days after receiving the second injection. There were 170 cases in total: 8 cases in the active vaccine cohort and 162 cases in those receiving the placebo. There were ten cases of severe disease, nine of which occurred in the placebo group. Just one patient of the 21,720 individuals who received the active vaccine became seriously ill with COVID-19. These are phenomenal results, translating to a vaccine efficacy of 95 percent in preventing symptoms of the disease.  In reviewing the graph plotting cases over time, the active vaccine and placebo response curves ascend in tandem until about ten days after administration, at which point they begin to dramatically diverge, the number of new cases in the vaccine group leveling off to near zero while the placebo curve continues to climb. It’s quite impressive. Based on this and other data, the FDA issued an EUA for the Pfizer BioNTech COVID-19 vaccine on December 11, 2020. I received my first dose one week later.

 

 

Almost simultaneously, Moderna released their phase 3 results, also published in the New England Journal of Medicine. Similar in design to the Pfizer trial, participants were aged 18 and older with similar inclusion and exclusion criteria. The trial was slightly smaller, with 14,134 volunteers receiving the active mRNA-1273 SARS-C0V-2 vaccine and 14,073 people receiving a placebo. Injections were administered 28 days apart. The primary endpoint was the occurrence of COVID-19 symptoms starting 14 days or more after the second injection. In this trial, 196 participants subsequently developed symptoms of COVID-19 infection: 11 cases in the vaccine cohort and 185 in the placebo group. There were 30 cases of severe disease and one death; all occurring in the placebo group. This translates to an efficacy rate of 94.1 percent at preventing symptomatic COVID-19 infection, and 100% efficacy at preventing severe disease or death. The response curve was similar to that seen in the Pfizer trial.

Neither trial included routine antigen testing, so the rate of asymptomatic COVID-19 infection following vaccination remains unknown, but is almost certainly a very small, or possibly even a non-existent, number of individuals. Bottom line: Both vaccines were extraordinarily effective at preventing serious infection with COVID-19.

 

 

 

This doesn’t mean there was no down side. In the trials, adverse events were common, occurring in the majority of those receiving the active vaccine. Side effects were more prevalent and more severe following the second dose. This makes sense and provides evidence that the vaccine is acting as intended. Because the immune system has already been primed from the first dose, when the second dose arrives the body responds rapidly, releasing inflammatory mediators that trigger the symptoms of headache, fatigue, muscle pain, and joint pain. Symptoms dissipate quickly because no actual virus is present to continue the cascade. People who fail to experience side effects should count themselves as lucky and not be worried. In phase 2 trials, the vaccines elicited brisk antibody responses in everybody who received them.

 

 

The most common reaction was injection site pain (remember being punched in the arm by your older brother as a kid?). Redness and swelling at the site occurred less frequently. Fatigue, headache, muscle pain (myalgia), joint pain (arthralgia), and chills were common; fever less-so. Symptoms resolved quickly over 24 hours. Relief occurred with both acetaminophen (Tylenol) and ibuprofen (Motrin, Advil). Theoretical concerns over the use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) during active COVID-19 infection or after vaccination have not been substantiated in human trials. Both are approved by the CDC for the treatment of post vaccine-related symptoms (although neither is recommended as a preventative).

 

 

 

Allergic reactions were uncommon and mild. There were no cases of anaphylaxis (the most serious type of acute allergic reaction) in either trial, although a few cases have been reported as the vaccines have come into broader use, on the order of 1 case of anaphylaxis per 90,090 vaccine doses administered. More than 70 percent of the anaphylactic reactions occurred within 15 minutes of the injection. The only absolute contraindication to receiving the vaccine is a prior serious or anaphylactic reaction to any of the components contained in it. Relative contraindications include serious allergic or anaphylactic reactions to any prior vaccine. Although pregnancy and breast-feeding women were excluded from the phase 3 trials, neither is felt to be a contraindication to vaccination. Currently, the CDC recommends that pregnant or breast-feeding women discuss the pros and cons of vaccination with their obstetrician or healthcare provider prior to receiving the vaccine.  There are ongoing studies to address these issues, as well as the use of vaccines in children and adolescents. For routine vaccinations, participants should be observed for 15 minutes following administration, increasing to 30 minutes for those with a history of vaccine allergy or anaphylaxis.

 

 

In general when discussing vaccines there are two issues regarding effectiveness: 1) direct protection (i.e., does the vaccine prevent symptomatic infection?); and, 2) Indirect protection (i.e., does the vaccine prevent transmission to others?). While the phase 3 trials determined a high degree of efficacy at preventing symptomatic illness, they did not answer the question as to whether vaccination prevents viral transmission in the absence of symptoms. Since we know that more severe illness is correlated to higher viral loads and a greater risk of transmission, it makes sense that a vaccine that prevents symptoms should also limit the spread of the virus to others, but this is not the same thing as proof.

Of the world’s nations, Israel has been the most efficient in rolling out the vaccine. Their highly-coordinated program began on December 20, 2020, and by early February had successfully vaccinated more than 75 percent of individuals aged 60 and older, and more than a quarter of those between the ages of 40 to 60, before opening up the program to everybody aged 16 and older on February 4, 2021. This is pretty amazing. Given the extent of air travel, it should be obvious that the only way for the world to defeat the pandemic is through a high degree of vaccination amongst all the world’s nations. In prepublication data released by Israel’s My Heritage lab, viral titers in those testing positive for the virus have been far lower across the board since initiation of the program compared to those found in the months of December and early January, suggesting that the vaccine does indeed lower the risk of transmission (lower viral loads = lower transmission risk).

Regarding the emerging strains of COVID-19 found in the UK, S. Africa, and Brazil, we are not flying blind. Theoretically, in the absence of a major mutation involving the spike protein, current vaccines should offer protection. Early data suggests that both the Moderna and Pfizer vaccines are highly effective against the UK strain (SARS-CoV-2 strain B.1.1.7) but less so against the S. African variant (SARS-CoV-2 strain B.1.351). This is important because the UK strain is more transmissible (and possibly more virulent) than current US strains, while the S African strain appears to be both more transmissible and more virulent. Both strains have been found in the US. Tweaking the vaccines to address issues of virulence and transmissibility is possible and will likely be necessary going forward. This does not mean that people should wait, skipping current versions until the next generation of vaccines are developed.

Vaccine caveats:

• Protection begins to take effect roughly 10 to 12 days of the first dose of both the Moderna and Pfizer vaccines, but best protection (95 percent) isn’t achieved until 10-14 days after the second dose. For the single shot Johnson & Johnson vaccine, protection begins after about 14 days and is maximized by 28 days. Expect individual variation.
• The vaccine does not affect subsequent viral antigen testing, but will result in a positive serology test for IgM and IgG antibodies against the COVID-19 spike protein.
• The duration of immunity following vaccination isn’t known, but follow up data suggests at least six months of protection against current strains according to Albert Bourla (Pfizer CEO).
• The mRNA vaccines should not be administered within two weeks of receiving any other vaccine (influenza, shingles, pneumococcal etc.)
• If for any reason the second shot is missed, it is permissible to obtain the second vaccine up to six weeks out from the first for both the Pfizer and Moderna vaccines.
• Given that the incubation time for symptomatic disease is shorter than the time required for active immunity to occur, the vaccine is ineffective as a prophylactic intervention after exposure to the virus.
• In such cases, vaccination should be deferred until completion of the quarantine period (exceptions: healthcare workers and residents of long-term care facilities and correctional facilities).
• In patients with symptomatic infection, vaccination should be deferred until recovery. There is no minimum interval time between recovery and vaccination, although data suggests that re-infection is extremely rare within 90 days of a primary infection.
• Vaccination is currently recommended in those who have recovered from infection with COVID-19. The timing of vaccination remains unclear (see above).
• Patients treated with monoclonal antibody therapy during a COVID-19 infection should wait 90 days or more before receiving the vaccine.
• Serious adverse reactions to the vaccine should be reported either directly to VAERS (https://vaers.hhs.gov/esubhelp.html) or through the V-Safe smartphone app (https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html).
• After vaccination, the ongoing use of masks, social distancing and safe hygiene practices need to continue. These practices limit the spread of not just COVID-19, but other illnesses ranging from influenza to the common cold. In public, it is impossible to know whether a maskless individual has undergone vaccination, has forgotten his/her mask, or is being willfully non-compliant. Until such time as mask recommendations are lifted by the CDC, all individuals should continue to use them in public areas.

 

 

 

 

Other COVID-19 Vaccines.

There are several other vaccines currently in widespread use, with the Johnson & Johnson vaccine having obtained recent US approval.  As opposed to the Moderna and Pfizer vaccines, the Johnson & Johnson version (AD26.COV2.S vaccine) employs a non-replicating common cold virus (Adenovirus 26) to deliver a stabilized gene encoding for the COVID-19 spike protein. While not as effective at preventing disease, it remains extremely effective at preventing serious illness, and has the advantage of requiring just a single injection. Furthermore, it can be stored in regular refrigerators whereas both mRNA vaccines require cold storage units (Moderna -15 to +5 F; Pfizer -76 to -115F).  An earlier study found the J&J vaccine to be 72 percent effective against current US strains; 57 percent effective against the S. African variant; and, 66 percent effective against the Brazilian variant.

There is also published data on the effectiveness of other vaccines, including the Gamaleya Sputnik V viral-vector vaccine used in Russia (efficacy 91.6 percent); the Oxford Astra-Zeneca (AZD1222) viral-vector vaccine in widespread use in the UK and Europe (efficacy 76%); the CanSino Biologics vaccine deployed primarily in China (efficacy 91 percent); and the Novavax (NVX-CoV2373) protein-based vaccine (efficacy 89.3 percent). Although efficacy varies, it’s important to note that all currently available vaccines have demonstrated near perfect efficacy in preventing hospitalization or death due to COVID-19. The former is a measure of whether the vaccine prevents any COVID-19 illness, the latter whether it prevents serious illness. All of the current vaccines are extremely effective at preventing death due to the virus, so take whichever one is available.

ACIP (Advisory Committee on Immunization Practices) has adopted the following prioritizations for vaccination based on need, exposure, and susceptibility:

• Phase 1a: healthcare workers and residents of long-term care facilities (21 million people).
• Phase 1b: people aged 75 and older, and essential frontline, non-healthcare workers (49 million people).
• Phase 1c: people aged 65 to 74, those aged 16 to 64 with high-risk medical conditions, and essential workers not designated in phase 1a or 1b (129 million people).
• Phase 2: all people aged 16 years and older not previously designated to receive the vaccine.

Distribution and administration vary by state. (Check the following guide for more information: https://www.today.com/health/how-register-covid-19-vaccine-state-state-guide-t205275.)

 

 

The final hurdle in putting the pandemic behind us will likely be overcoming vaccine hesitancy. From September to December the percentage of people reporting that they were “absolutely certain” or “very likely” to undergo vaccination increased from 39 to 49 percent, with the largest increase coming in those aged 65 and older. This is great, but still leaves half the nation uncertain. A separate, more recent poll reported that 31 percent of Americans plan to take a “wait and see” approach, with 20 percent expressing “extreme reluctance” to receive the vaccine.

There are several reasons why waiting is not a good idea. First, the vaccine has been thoroughly vetted. It’s safe. It’s effective. More than 47 million Americans have already received at least one dose, with nearly 230 million doses administered worldwide. If there were any near-term, rare adverse events associated with the vaccine, they would have been discovered by now. Second, recall that at least 70 percent of the population requires immunity before herd immunity applies to the rest. Thus, we need an additional 220 million Americans to be vaccinated before we can literally begin to breathe easier. Waiting means that more Americans will become sick and more Americans will die. Third, the longer the virus exists in the community, the better chance it has at developing resistance to current treatments. As the available pool of non-immune individuals shrinks, the pressure applied to the virus to mutate increases. If a major mutation to the spike protein occurs rendering current vaccines ineffective, this will serve to move all of us back to square one. The best way to avoid this scenario is in vaccinating as many people as possible in as short a time as possible. Hesitation places the entire population at risk. Fourth, over a half million US deaths. Enough is enough.

Finally, consider the following:

• If COVID-19 had faded into the ether in a manner similar to other serious coronavirus outbreaks (SARS in 2003 and MERS in 2013) then the vaccine wouldn’t have become necessary, but it didn’t.
• If social distancing, handwashing, and masking had been widely adopted and the spread of the virus controlled then the vaccine wouldn’t have become necessary, but this didn’t happen either.
• If the amazing components of our own immune systems were adequate to prevent serious illness and death, the vaccine wouldn’t have become necessary, but they’re not.
• If taking vitamin D, vitamin C, zinc, hydroxychloroquine, ivermectin, essential oils, or homeopathic medicines actually worked to prevent illness or progression then the vaccine wouldn’t have become necessary, but they don’t.
• If the heroic efforts of millions of healthcare workers putting their own lives at risk to save members of their communities had prevented Americans from dying then the vaccine wouldn’t have become necessary, but they weren’t.

Overcoming vaccine anxiety is difficult, but overcoming the death of a loved one is far more difficult. The term “civic duty” refers to the responsibilities reasonably expected from the members of a society in keeping with the principle that individuals are obligated to service in exchange for the rights and protections offered by the collective. In the case of COVID-19, if we wish to return to the freedoms and privileges previously enjoyed then we must all do our part and get vaccinated when our turn arrives. Until then, stay healthy my friends.

 

 

References:

1. A. Jackson et al., “An mRNA Vaccine against SARS-CoV-2 — Preliminary Report,” NEJM, July 2020; DOI: 10.1056/NEJMoa2022483.
2. R. Braden et al., “Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine,” NEJM 2021; 384 (5): 403-16.
3. Kai Wu et al., “Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine — Preliminary Report,” NEJM, Feb 2021; DOI: 10.1056/NEJMc2102179.
4. J. Anderson et al., “Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults,” NEJM 2020; 383 (25): 2427-38.
5. Fernando Polack et al., “Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine,” NEJM 2020; 383 (27): 2603-15.
6. Sharon Amit et al., “Early Rate Reductions of SARS-CoV-2 Infection and COVID-19 in BNT162b2 Vaccine Recipients,” Lancet, Feb 2021; doi.org/10.1016/ S0140-6736(21)00448-7.
7. Yang Liu et al., “Neutralizing Activity of BNT162b2-Elicited Serum — Preliminary Report,” NEJM, Feb 2021; DOI: 10.1056/NEJMc2102017.
8. Ella Petter et al., “Initial Real World Evidence for Lower Viral Load of Individuals Who Have Been Vaccinated by BNT162b2,” (prepublication), Feb 7, 2021.
9. Denis Logunov et al., “Safety and efficacy of an rAd26 and rAd5 Vector-Based Heterologous Prime-Boost COVID-19 Vaccine: An Interim Analysis of a Randomised Controlled Phase 3 Trial in Russia,” Lancet, Feb 2021; doi.org/10.1016/ S0140-6736(21)00234-8.
10. Sadoff et al., “Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine,” NEJM, Feb 2021; DOI: 10.1056/NEJMoa2034201.
11. Keech et al., “Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine,” NEJM 2020; 383 (24): 2320-32.
12. Merryn Voysey et al., “Single Dose Administration, and the Influence of the Timing of the Booster Dose on Immunogenicity and Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine,” (Lancet prepublication), Feb 1, 2021.
13. David Paltiel et al., “Clinical Outcomes Of A COVID-19 Vaccine: Implementation Over Efficacy,” Health Affairs 2021; 40 (1): 42–52.
14. Kathleen Dooling et al., “The Advisory Committee on Immunization Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine — United States, December 2020,” MMWR 2021; 69 (51-52): 1657-60.
15. Lisa Rosenbaum, “Escaping Catch-22 — Overcoming Covid Vaccine Hesitancy,” NEJM, Feb 2021; DOI: 10.1056/NEJMms2101220.
16. Lisa Rosenbaum, “No Cure without Care — Soothing Science Skepticism,” NEJM, Feb 2021; DOI: 10.1056/NEJMms2101989.
17. Kimberly Nguyen et al., “COVID-19 Vaccination Intent, Perceptions, and Reasons for Not Vaccinating Among Groups Prioritized for Early Vaccination — United States, September and December 2020,” MMWR 2021; 70 (6): 217-22.