Wide World of Vaccines

The Boosters Are Coming! The Boosters Are Coming!

Column Editor: Christopher Harrison, MD | Professor of Pediatrics, UMKC School of Medicine | Clinical Professor of Pediatrics, University of Kansas School of Medicine

Vaccine to boost titers will be the norm, sometime around eight months post your last dose if you were initially fully immunized, or at any time if you were previously infected but not yet vaccinated. Why?

The sobering news this past three weeks includes Delta variants comprising >93% of U.S. cases; the U.S. daily case rate is now comparable to the deep winter 2020 surge, with >1,200 cases a day. The unvaccinated, whether previously infected or not, now make up more than 90% of deaths and also hospitalizations. Hospitalizations are now among mostly 25- to 35-year-olds and include more children, too.

Hospitalizations dramatically increased, particularly in low vaccination states (looking at you Missouri and Kansas, as well as Arkansas, Louisiana, Mississippi and Florida). Florida has the worst numbers, yet their governor has forbidden mask mandates even for schools, threatening to withhold funding if schools require masks. We have lost ground in the last three months. But what does the future hold?

It is scary to consider that football season will start in late August (nearly half of those attending likely not vaccinated) and schools have reopened (rules seem to still be evolving and over two-thirds of children are unvaccinated). How alarmed should we be? Well, the U.S. government was concerned enough to ask the FDA to evaluate and approve use of mRNA boosters in select severely immunocompromised mostly cancer patients. These patients don’t need a prescription or a letter from a doctor for the booster, but must state that they have impaired immune systems. Table 1.

Recent data suggest a long-lasting surge if vaccine uptake does not improve and suggest the need for both more stringent use of masking and social distancing again, plus boosters for all (eventually). News reports on Aug. 16 indicate that everyone will be eligible eight months post their last dose, as long as there are no hold-ups in the FDA review. But if everyone showed up for boosters in September, there would be a real crunch, so initially boosters will be for immunocompromised and elderly groups, then non-immunocompromised later. Likely the first non-immunocompromised to be eight months out will be first responders, then groups will follow the scheme of groups paralleling the initial rollout. 

1) Kentucky data. The CDC reported Kentucky patients, previously infected during October to December 2020, likely with Wuhan or Alpha virus, and now reinfected in May to June 2021 (presumed with Delta virus).¹ They compared 246 unvaccinated now reinfected persons to 492 now fully vaccinated persons with breakthrough infections. The unvaccinated, previously-infected were significantly more likely to get a new SARS-CoV-2 infection (OR = 2.34; 95% CI = 1.58–3.47). Fully vaccinated was defined as a single dose of Janssen (Johnson & Johnson) or a second dose of an mRNA vaccine (Pfizer-BioNTech or Moderna).

• Bottom line: All eligibles need vaccine, whether previously infected or not. Every new infection may give birth to a new, more contagious, or more deadly variant, e.g., the new “Delta plus” variant. We need to minimize new infections with greater vaccine uptake.

2) Israel. Israel was the most aggressive developed country in immunizing its population and used Pfizer’s mRNA vaccine. By February 2021, over 85% of their eligible population was fully vaccinated, which broke their Beta virus surge. Herd immunity seemed to be in place. Then came Delta. Breakthrough infections started to appear in the fully vaccinated elderly, suggesting a problem with immunity in the elderly.²

• Bottom line: The threshold neutralizing titer needed for protection is not yet known, but data from a group of mRNA vaccine studies are soon to be released with “neuts” seeming reasonable predictors of protection.

3) Oregon. Live-virus neutralizing assays (the most valid neutralizing assay) on serum from 14 days after second doses in non-immunocompromised vaccinees showed geometric mean titers (GMT) 85% lower in the elderly than the young, and borderline titers against Gamma virus in even the young.³ Table 2. If neutralizing titers of at least 100, maybe even 200, are needed for protection, as seems likely, only 30% of 20- to 29-year-olds and only 9% of 70- to 62-year-olds would be protected against the Gamma virus with near peak-post vaccine titers like those above. 

• Bottom line: Consider that titers fall over six months post vaccine. The Delta virus is now dominant, but the Gamma virus has a U.S. foothold, so higher titers like those from booster doses at six to nine months, seem needed at least in the elderly and immunocompromised, unless “neuts” turn out to be merely surrogates of cell-mediated memory, which could be the real protective element.⁴

4) South America. Finally, the Gamma virus caused an outbreak of symptomatic COVID-19 in miners from French Guiana.⁵ Most miners were fully immunized and otherwise healthy. They lived in semi-closed camps and were in close proximity in underground mines as extra risk factors. Nevertheless, an attack rate of 60% in the fully immunized was unexpected but was less than the 75% attack rate in the unvaccinated miners. Thankfully, none were hospitalized.

• Bottom line: Higher titers are needed to neutralize Gamma, much like the Delta virus, allowing the Gamma virus to show Delta-like abilities to cause symptomatic breakthrough infections. That’s more reason boosting titers with an additional dose looks to be in our future.    

5) Israel part II. Israeli data seems predictive for the U.S. Delta surge but with a twist. They had almost no cases and no deaths for two weeks in late May (honeymoon). Myo/pericarditis cases mostly in young males all seem short lived with no identified sequelae four to six months later. Then the Delta virus arrived in early June, heralding increased infections in unvaccinated and breakthrough infections in vaccinated patients. Now an explosive rise is occurring in cases and hospitalizations, mostly in the elderly and those with underlying conditions, but the twist is that most are fully vaccinated. And severe cases are mostly in those immunized more than six months ago. Why so many breakthroughs? The Israelis hypothesize that because Delta requires four times as much neutralizing antibody, immunity may be waning below the threshold needed to protect against Delta virus. So, they began booster doses in late July, expecting three to four-fold titer rises after boosting. They hope to break the Delta surge by Sept. 1, 2021.

• Bottom line: Stay tuned. This could be the real-world data to tell us how well the U.S. booster initiative will work.

Table 1. Immunocompromised conditions that qualify for mRNA booster dose.

Source: CDC: COVID-19 Vaccines for Moderately to Severely Immunocompromised People

Table 2. Neutralizing titers* against the Wuhan original SARS-CoV-2 virus and the Gamma variant 14 days after the second dose (near peak) of Pfizer mRNA vaccine.

* A neutralizing titer of 100 to 200 has been theorized as potential surrogate of protection.

Data source: Reference 3, JAMA Online

References:

1. Cavanaugh AM, et al. Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination — Kentucky, May–June 2021. Morbidity and Mortality Weekly Report. Early Release / Vol. 70 Aug. 6, pp 1-4. 2021.
2. Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021;397. (10287):1819-1829.
3. Bates TA, et al. Age-dependent neutralization of SARS-CoV-2 and P.1 variant by vaccine immune serum samples. JAMA Online. July 21, 2021.
4. Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. Published online May 17, 2021.
5. Vignier N, et al. Breakthrough infections of SARS-CoV-2 Gamma variant in fully vaccinated gold miners, French Guiana, 2021. Emerg Infect Dis. 2021 Oct [date cited]. https://doi.org/10.3201/eid2710.211427.