Evaluating SARS-CoV-2 Vaccine Efficacy With Rapid Antibody Assays

More than 180,000 deaths have occurred in the U.S.A. due directly to COVID-19 and/or associated complications. Remarkable advancement in diagnostics and treatment have been achieved to date, but further work is needed. Specifically, the availability of effective and safe vaccines is at the threshold of medical progress.

With regards to vaccine development and availability, there are currently numerous trials in progress to address the efficacy and safety issues. The prominent forms of prospective vaccines under development encompass (in descending frequency): those consisting of viral protein subunits, recombinant viral vectored candidates, nucleic acid-based vaccines (mRNA and plasmid DNA) , and less frequently inactivated virus vaccines, virus like particles, and live attenuated virus vaccines (1). Each has associated benefits and deficits. For example, let’s briefly review some aspects of the use of a live-attenuated viral vaccine. One advantage of both live-attenuated viral vaccines and inactivated viral vaccines, in contrast to viral protein subunit vaccines, is that they express a range of native viral antigens, including surface antigens that can induce confirmation-dependent antibody responses (2,3). However, unlike inactivated viral vaccines, historically, individuals with immunodeficiencies who received live attenuated viral vaccines at times developed a variant of the disorder being vaccinated against (e.g. polio, ref. 4 ). In addition, with the documented immunosenescence associated with older individuals, this may be an issue of concern. Furthermore, there are 4 human coronaviruses that cause a minority of  the common cold and normally, cross-reactive T cell induction (that target conserved sequences common to different human coronaviruses) during such infections occur. The cross-reactive T cell development can play a role in limiting the effectiveness of a subsequent live attenuated viral vaccine administration.

Although a large investment in vaccine development and distribution has occurred, initial distribution will probably be limited to those with the greatest  need. These vaccine recipients would include: healthcare workers, first responders, those over 65 years old and/or those with increased probable morbidity due to pre-existing medical conditions (e.g. diabetes, heart disease, cancer, respiratory disorders, etc.). Next in line would be the general healthy population. It is estimated that the group to receive the first vaccines number 110 million, while those allocated to be vaccinated later are 206 million individuals (5). With such large populations of vaccine recipients, it is predicted that it will take several months to distribute and administer the approved vaccines (6). 

The role and importance of point of care (POC) rapid SARS-Covid-2 antibody detection assays cannot be overemphasized. Even after the release of SARS-CoV-2 viral vaccines, the identification of infected individuals will remain an important goal. This identification is of the utmost importance in order to guide medical treatment, initiate quarantine procedures when indicated and the process of viral surveillance through contact tracing in order to prevent further viral transmission. Such rapid antibody detection assays can be an integral component of population surveillance protocols in order to determine which population centers and geographic areas are still susceptible to the pandemic and may require increases in vaccine distribution (7).

There is a bit of controversy in the literature about COVID-19 post-convalescent IgG antibody duration and prevention of recurrent infections. Several reports have demonstrated that anti-SARS-CoV-2 IgG antibodies are detectable for several months after COVID-19 recovery (8-10). However, the magnitude of the IgG response differs depending on disease severity. Long et al and Ibarrondo and colleagues demonstrated respectively that a rapid decay in anti-SARS-CoV-2 viral IgG occurs relatively rapidly in patients who had asymptomatic disease and mild disease in association with longer viral shedding periods presumably due to an attenuated immune response (8, 10). In addition, Long et al demonstrated that symptomatic patients synthesized higher levels of anti-viral IgG antibodies and had a lower frequency of negative seroconversion than asymptomatic patients (10). Of note and in contrast to the aforementioned studies, others demonstrated that symptomatic patients with COVID-19 maintained relatively high levels of anti-viral IgG titers and viral neutralizing antibodies throughout the 26 week observation period. Furthermore, by performing studies for more than 6 months, these researchers observed that the humoral immune response to SARS-CoV-2 in symptomatic COVID-19 patients is prototypical for viruses. Specifically, this is characterized by an early expansion phase followed by an intermediate contraction phase (after 9 weeks post symptom onset) and a sustained memory phase. They pointed out, studies that terminated their observation period earlier than 6 months, but extrapolated a long-term trend based on the contraction phase without considering or determining the memory phase may not elucidate the full immunologic response in patients that recovered from a symptomatic infection. These investigators documented the contraction period for anti-viral IgG titers began at about 9 weeks post symptom onset and was relatively stable until the final assessment at 26 weeks. Of note, the temporal discrepancy is evident when assessing the duration of the defined contraction period. The defined contraction period surpasses the results of recent reports that demonstrated anti-viral IgG decay within 90 days of symptom onset. Also, longer periods of significant antiviral IgG titers have been demonstrated in other human corona viral diseases such as the severe acute respiratory syndrome (SARS). SARS has been characterized by IgG viral neutralizing antibodies that persist for greater than 2 years in patients that have fully recovered. Thus, further research is required to fully elucidate the duration of anti-SARS-CoV-2 IgG and the potential extent of immunologic protection evident following full recovery from COVID-19. 

Does protective immunity develop, and to what extent does it develop following recovery from COVID-19? This question requires further elucidation. Animal studies have demonstrated that in a rhesus macaques animal model, after initial clearance of SARS-CoV-2 infection (including pneumonia), upon viral re-challenge, there was a significantly lower viral load in the respiratory tract in comparison to the primary infection. Furthermore, the results of the study suggested that the primary SARS-CoV-2 infection induced protective immunity against re-exposure (11). 

The same researchers developed several candidate DNA vaccines and tested their efficacy in the rhesus macaques SARS-CoV-2 animal model (12). They demonstrated that vaccinated animals developed humeral and cellular immune responses including viral neutralizing antibodies at concentrations equivalent to levels identified in animals with primary SARS-CoV-2 infections. In addition, vaccinated animals were exposed to SARS-CoV-2 virus and demonstrated a 3 fold or greater reduction in respiratory tract viral loads compared to their unvaccinated counterparts (12). 

From accumulated human studies, we know that IgG anti-viral neutralizing antibodies are synthesized to considerable levels in those with symptomatic or severe SARS-CoV-2 infections (1). This is further evident in the beneficial clinical outcome demonstrated if convalescent plasma, containing high titers of IgG viral neutralizing antibodies, is administered to patients with COVID-19 within 72 hours of hospitalization (13). These factors are suggestive, although not conclusive, that the synthesis of significant titers of IgG viral neutralizing antibodies by the immune system contributes to decreased morbidity and pathogenesis. 

Due to the predicted delay in vaccine acquisition, distribution and administration (5), the use of  SARS-CoV-2 antibody detection assays may also play a prominent role in assisting the delineation of which individuals may need to be vaccinated immediately or can safely be vaccinated at a later date. If there is a lack of serum IgG anti-viral antibodies present as detected by a rapid antibody assay,  then these individuals have a lack of current humeral immunologic protection and merit consideration for early vaccine administration. Furthermore, once further research demonstrates the duration of  specific serum IgG anti-viral antibodies in patients who recovered from COVID-19 and that during that duration, SARS-CoV-2 reinfection is prevented, then these individuals may be able to delay vaccine administration until their serum anti-viral IgG levels begin to wane (14).

After the initiation of vaccination programs, specific antibody assays may further be utilized to confirm vaccine induced seroconversion and the duration immunologic protection imparted by the SARS-CoV-2 viral vaccine administered (14).

References

  1. Jeyanathan M. Nature Rev Immunol (Sept. 4), 2020.
  2. Qamar TU. J Transl Med 17: 362,2019.
  3. Watanabe T. Science 369: 330, 2020.
  4. Heiman S. Immunol Res 66: 437, 2018.
  5. Cohen J. Science Mag (June 29), 2020.
  6. Curley C. Healthline (Aug. 4), 2020.
  7. Alter G. NEJM (Sept 1), 2020.
  8. Ibarrondo F. NEJM (Sept 12), 2020.
  9. Co WC. NEJM (Sept 14), 2020.
  10. Long Q-X. Nat Med (June 18), 2020.
  11. Chandrashekar A. Science 369:813,2020.
  12. Yu J. Science 369:806,2020.
  13. NIH COVID-19 Treatment Guidelines: Convalescent Plasma (July 17), 2020.
  14. AAP News:  https://www.aappublications.org/news/2020/05/22/covid19antibodies052220